THE  LIBRARY 

OF 

THE  UNIVERSITY 

OF  CALIFORNIA 

DAVIS 

GIFT  OF 

KARL  FRTJEDERICH  MEYER 


PROTEIN  THERAPY 

AND 

NONSPECIFIC  RESISTANCE 


THE    MACMILLAN   COMPANY 

NEW  YORK    •    BOSTON   •    CHICAGO   •    DALLAS 
ATLANTA   •   SAN  FRANCISCO 

MACMILLAN  &  CO..  LIMITED 

LONDON   •    BOMBAY    •    CALCUTTA 
MELBOURNE 

THE  MACMILLAN  CO.  OF  CANADA,  LTD. 

TORONTO 


PROTEIN   THERAPY 

AND 

NONSPECIFIC    RESISTANCE 


BY 

WILLIAM  F.  PETERSEN,  M.D. 

ASSOCIATE  IN  PATHOLOGY,  UNIVERSITY  OF  ILLINOIS, 
COLLEGE  OP  MEDICINE,  CHICAGO,  ILL. 


WITH  AN  INTRODUCTION  BY 

JOSEPH  L.  MILLER,  M.D. 

PROFESSOR  OF  MEDICINE,  RUSH  MEDICAL  COLLEGE, 
UNIVERSITY  OF  CHICAGO,  CHICAGO,  ILL. 


J13eto  gotfe 

THE  MACMILLAN  COMPANY 
1922 

All  rights  reserved 


LIBRARY 

UNIVERSITY  OF  CALIFORNIA 
DAVIS 


FEINTED  IN   THE  UNITED  STATES  Or  AMERICA 


COPYRIGHT,  1922 
BY  THE  MACMILLAN  COMPANY. 


Set  up  and  printed.     Published  January,  1922. 


Press  of 

J.  J.  Little  &  Ives  Company 
New  York,  U.  S.  A, 


M.  b.  L. 


"Thus  there  exists  a  fashion  in  medicine,  as  in  the  other  affairs 
of  life,  regulated  by  the  caprice  and  supported  by  the  authority  of 
a  few  leading  practitioners,  which  has  been  frequently  the  oc- 
casion of  dismissing  from  practice  valuable  medicines,  and  sub- 
stituting others  less  certain  in  their  effects  and  more  questionable 
in  their  nature.  As  years  and  fashions  revolve,  so  have  these 
neglected  remedies,  each  in  its  turn,  rise  again  into  favour  and 
notice,  whilst  old  receipts,  like  old  almanacks,  are  abandoned  until 
the  period  may  arrive,  that  will  once  more  adapt  them  to  the 
spirit  and  fashion  of  the  times.  Thus  it  happens  that  most  of 
our  "New  Discoveries"  in  the  Materia  Medica  have  turned  out  to 
be  no  more  than  the  revival  and  adaptation  of  ancient  practices." 

— From  the  Introduction  of  Paris' 
Pharmacologia,  New  York,  1830. 


PREFACE 

The  conception  that  the  organism  in  its  resistance  to  disease  and  de- 
fense against  bacterial  invasion  depends  on  biologic  reactions  essen- 
tially specific  has  dominated  medical  thought,  medical  experimentation, 
and  medical  practice  for  a  period  of  over  thirty  years.  They  have 
been  years  of  tremendous  progress  in  the  theory  and  the  practice  of 
medicine.  Indeed,  the  advance,  as  contrasted  with  that  of  the  ages 
gone  before,  has  been  so  vast  and  far-reaching  that  we  have  by  as- 
sociation come  to  regard  this  progress  and  the  underlying  trend  of 
medical  thought  and  theory,  i.e.,  specificity,  as  practically  identical. 

The  idea  of  therapy  on  a  nonspecific  basis  seems  therefore  at  first 
glance  a  step  backward,  investigation  of  such  a  subject  illogical,  if 
nothing  worse.  And  as  we  might  expect  on  such  premises,  the  present 
interest  in  nonspecific  therapy  did  not  originate  on  the  basis  of  a  con- 
vincing theory  or  promising  laboratory  experimentation.  It  was  the 
clinic  that  forced  upon  our  attention  certain  therapeutic  results  which 
could  not  be  ignored,  results  so  startling  in  many  ways  that  our  con- 
ception of  the  mechanism  of  recovery  from  disease  has  had  to  be  re- 
cast. 

The  theoretic  basis  to  account  for  the  results  has  been  lacking, 
at  least  our  current  conception  of  immunity  and  of  resistance  to  dis- 
ease has  been  found  wholly  inadequate  to  explain  the  clinical  results. 
This  seeming  empiricism,  this  lack  of  exact  knowledge  concerning  the 
mechanism  of  the  nonspecific  reaction  has  been  the  chief  point  of  at- 
tack for  whatever  criticism  has  been  presented.  A  brief  examina- 
tion of  the  subject  will,  however,  reveal  that  nonspecificity  need  not 
be  as  illogical,  theoretically,  as  a  cursory  view  might  lead  us  to  be- 
lieve. If  we  keep  the  focus  of  our  attention  on  the  reaction  of  the 
body  to  injury — on  inflammation — we  find  that  this  reaction,  no  mat- 
ter how  produced, — be  it  bacterial  invasion,  intoxication,  or  trauma, — 
is  fundamentally  similar  under  all  circumstances.  The  type  of  cellular 
reaction  may  vary  to  some  degree,  the  amount  and  composition  of 
the  exudate  may  differ,  but  the  basic  alterations  are  always  alike. 
We  deal  with  a  consistent  effort  to  dilute  the  noxious  agent,  to  re- 
move it  by  intracellular  or  extracellular  digestion,  to  neutralize  it; 
these  failing,  then  to  wall  it  off,  to  put  it  outside  of  the  current  of 
normal  tissue  activity. 

If  now  we  seek  to  alter  this  process  therapeutically  we  have  two 
distinct  avenues  of  approach.  The  one  is  interested  solely  in  the  cause 
of  the  inflammatory  reaction — if  a  bacterium,  to  produce  an  anti- 

ix 


x  PREFACE 

bacterial  agent — if  a  toxin,  to  produce  an  antitoxin — if  a  chemical,  to 
introduce  a  neutralizing  substance.  We  see  at  once  that  in  so  far  as 
the  causes  of  inflammation  may  be  unlimited,  so  our  specific  agents 
would  have  to  be  unlimited. 

The  alternative  lies  in  the  endeavor  to  alter  the  inflammatory  re- 
action of  the  body  itself.  We  may  seek  to  augment  its  natural  course, 
hastening  autolysis  and  resorption,  or  attempt  the  reverse,  retarding 
autolysis  and  stimulating  the  reparative  phases,  as  we  may  wish.  This 
is  a  true  "ergotropie,"  as  v.  Groer  has  termed  it,  a  therapeusis  whereby 
we  alter  the  reaction  of  the  organism  to  the  etiologic  agent,  rather  than 
endeavoring  to  influence  the  causative  factor  of  the  inflammatory 
process  directly.  Such  a  therapy  must  of  necessity  be  nonspecific  in 
the  immunological  sense. 

Perhaps  it  will  be  well  to  make  clear  at  the  very  beginning  that 
the  nonspecific  reaction  brings  into  play  no  new  and  heretofore  un- 
known factors  of  resistance.  It  deals  largely  with  reactions  previously 
studied  and  which  have  always  been  employed  by  the  organism  in 
overcoming  disease,  with  or  without  our  conscious  interference.  It 
does  deal,  however,  with  the  stimulation  of  these  forces  and  when  skill- 
fully invoked  brings  to  bear  a  summation  of  the  varied  measures  of 
defense  of  which  the  organism  is  possessed.  It  is  quite  probable 
that  these  potential  forces  may  have  been  latent  or  held  in  abeyance 
until  the  nonspecific  reaction  brings  them  into  activity.  It  has  been 
observed  that  the  antibodies  (agglutinins,  precipitins,  opsonins,  etc.) 
are  "shed"  or  cast  off  from  the  cells  after  a  nonspecific  injection;  so, 
too,  fibrinogen  and  thrombokinase  are  increased  and  a  variety  of 
enzymes  are  poured  out  from  the  cells  into  the  circulation. 

If  nonspecific  therapy  is  after  all  merely  a  method  that  deals 
with  heretofore  known  reactions  we  must  be  prepared  to  accept  the 
probability  that  it  obeys  all  the  commonly  observed  laws  of  biologic 
reactions.  If  we  regard  it  as  a  method  of  stimulation — plasma  activa- 
tion— it  follows  that  it  can  only  be  effective  when  the  protoplasm  is 
still  in  fit  condition  to  respond  to  stimulation.  Once  the  stage  of  ex- 
haustion has  been  reached  the  mere  irritation  of  the  nonspecific  agent 
is  no  longer  able  to  bring  about  any  alteration  in  the  disease  process 
other  than  an  aggravation. 

The  observations  that  have  been  made  the  basis  of  this  monograph 
have  been  gathered  partly  at  first  hand,  both  clinically  and  ex- 
perimentally, more  largely  from  a  survey  ^of  such  literature  as  the 
exigencies  of  the  war  have  made  available  to  me.  The  summarizing  of 
our  present  knowledge  in  this  particular  field  has  seemed  of  some  pos- 
sible value,  not  with  the  idea  of  popularizing  a  new  therapeutic  meas- 
ure but  rather  in  stimulating  interest  in  a  direction  that  seems  to 
offer  decided  possibilities  of  advance.  I  have  therefore  merely  indi- 
cated some  of  the  methods  at  present  employed  in  nonspecific  therapy 
without  effort  to  define  precise  modes  of  application  or  indications  for 


PREFACE  xi 

therapeutic  use.  On  the  other  hand  I  have  endeavored  to  present  the 
possible  theoretical  basis  and  some  of  the  collateral  fields  of  ap- 
plication as  fully  as  our  present  knowledge  will  permit.  A  great  num- 
ber of  problems  and  questions  of  decided  practical  importance  could 
unfortunately  be  merely  mentioned  without  further  discussion. 

In  the  presentation  of  the  clinical  results  so  far  reported  I  have 
endeavored  to  maintain  an  attitude  of  caution.  If  at  times  I  have 
erred  from  pure  objectivity  I  must  accept  the  blame  in  perhaps  pre- 
senting the  clinical  reports  of  a  number  of  observers  whose  enthusiasm 
has  perchance  outweighed  their  judgment.  We  must  remember  that 
it  was  the  clinic  that  directed  the  attention  to  this  form  of  therapy. 

During  the  short  space  of  seven  years  nonspecific  therapy  has 
gained  a  firm  foothold  in  clinical  thought  and  practice;  to-day  it  is 
recognized  even  by  immunologists  as  one  of  the  factors  in  resistance 
to  disease.  Whether,  as  Much  surmises,  nonspecific  resistance  and 
nonspecific  immunity  are  of  greater  importance  to  the  organism  than 
are  the  specific  forces  should  not  for  the  time  being  concern  us;  our 
interest  should  be  centered  on  applicability,  methods  and  causes.  Only 
when  the  vast  field  has  been  partially  explored  will  it  be  permissible 
to  judge  the  ultimate  importance. 

While  I  have  retained  the  name  Protein  Therapy,  it  should  be 
recognized  that  Protein  Therapy  deals  merely  with  one  of  a  large 
group  of  agents  which  can  be  used  to  elicit  the  nonspecific  reaction. 
Other  terms  have  been  applied — "Colloid  Therapy";  "Shock  Therapy"; 
"Foreign  Protein  Therapy";  "Heterovaccine  Therapy,"  but  inasmuch 
as  it  is  the  reaction  of  the  patient  that  is  of  importance,  not  the  sub- 
stance that  causes  the  reaction,  a  name  much  broader  in  its  signifi- 
cance should  be  used.  "Ergotropie,"  the  term  coined  by  v.  Groer,  is 
possibly  correct  and  most  expressive  in  that  it  emphasizes  the  re- 
action of  the  patient  and  properly  ignores  the  substance  that  causes 
the  reaction. 

How  far-reaching  the  field  of  nonspecific  stimulation  is  in  its  vari- 
ous modifications  becomes  apparent  from  a  consideration  of  the  num- 
ber and  the  character  of  the  agents  which  have  been  employed  to 
bring  about  therapeutic  results.  Even  the  purely  physical  and  me- 
chanical means — including  irradiation,  electricity,  baths,  massage,  etc. 
—must  be  included  in  the  survey  because  in  some  measure  they  bring 
about  changes  in  the  organism  similar  in  character  to  those  that  we 
shall  discuss  in  the  following  pages. 

To  Dr.  Otto  L.  Schmidt,  who  very  kindly  read  the  manuscript  and 
made  a  number  of  suggestions,  and  to  Dr.  Joseph  L.  Miller,  whose  in- 
terested cooperation  I  have  at  all  times  enjoyed,  I  am  under  grateful 
obligation.  To  Miss  Josephine  Bates  of  New  York  I  am  indebted  for 
her  careful  revision  of  the  bibliography. 

W.  F.  P. 


INTRODUCTION 

Seven  years  have  elapsed  since  the  attention  of  the  profession  was 
first  seriously  attracted  to  the  nonspecific  character  of  vaccine  therapy. 
The  literature  previous  to  this,  however,  contained  considerable  evi- 
dence suggesting  this  viewpoint.  Immunologists  and  members  of  the 
medical  profession  were  so  engrossed  with  the  idea  that  favorable  re- 
sults could  only  be  secured  by  specific  means  that  this  evidence  was 
largely  ignored. 

As  a  consequence  of  the  stimulation  given  by  the  earlier  investi- 
gators there  has  developed  an  extensive  literature  upon  this  subject. 
A  considerable  number  of  agents,  many  of  them  proprietary  in  char- 
acter, have  been  recommended  as  possessing  special  virtues.  The 
marked  febrile  reaction  with  its  accompanying  shock  inherent  in  the 
more  toxic  substances  first  used  in  this  form  of  therapy  prevented  its 
widespread  adoption.  This  may  be  considered  as  most  fortunate.  It 
is  well  that  this  procedure  was  restricted  until  more  unanimity  of 
opinion  was  established  in  regard  to  indications,  dosage  and  therapeutic 
value.  Indiscriminate  use  of  any  new  and  more  or  less  untried  method 
of  treatment,  especially  when  associated  with  possible  danger,  is  to  be 
discouraged.  Its  application  in  conditions  where  it  is  not  indicated 
would  tend  to  place  it  in  bad  repute  and  might  delay  the  development 
of  a  method  of  real  but  possibly  limited  value. 

It  is  opportune,  therefore,  that  this  subject  be  fully  presented  to 
the  profession  by  some  one  familiar  with  the  problems  of  immunity, 
well  informed  upon  the  literature  of  Protein  Therapy,  and  who  at  the 
same  time  has  enjoyed  clinical  experience  in  its  application.  Dr.  Pe- 
tersen,  in  conjunction  with  Dr.  Jobling,  were  the  American  pioneers  in 
this  work.  Through  their  carefully  controlled  clinical  observations  and 
logical  deductions  they  have  stimulated  other  investigators. 

To  all  those  interested  in  the  treatment  of  infections — and  this 
includes  both  physicians  and  immunologists — this  book  will  be  most 
welcome,  presenting  as  it  does  in  a  comprehensive  manner  a  com- 
plete analytical  review  of  the  subject,  which  will  be  of  assistance  in 
furnishing  a  basis  for  further  carefully  controlled  studies. 

JOSEPH  L.  MILLER. 


CONTENTS 

PAGE 

INTRODUCTION >    >    >:    ;.    xiii 

THE  METHOD 

CHAPTER  I 
HISTORICAL 1 

Therapy  of  typhoid  fever  by  Fraenkel  and  Rumpf — Specificity  of  Tuberculin 
— Fixation  abscess  of  Fochier — Nucleic  acid — Colloidal  metals — Auto- 
serotherapy  —  Tumor  treatment  —  Leukocytic  extracts  —  Paraspecific 
therapy  of  Paton — Deutschmann  serum — Schafer  vaccine — Intravenous 
gonocvoccus  vaccine — Intravenous  typhoid  vaccine  in  typhoid  fever — 
Heterobacterio-therapy  of  Renaud  and  Kraus— Protein  split  products — 
Milk— Recognition  of  the  nonspecific  factor  in  therapy. 

CHAPTER  II 
THE  NONSPECIFIC  AGENTS 12 

Counterirritation:  Cautery,  Seton,  Fontanelle,  Blisters,  Rubifacients — 
Serums:  Normal,  human,  horse,  sheep,  beef,  goat,  chicken  serum,  etc. 
Immune  Serums:  Human  convalescent  serum — Antimeningitis,  anti- 
dysentery  and  antistreptococcus  serum — Diphtheria  and  tetanus  anti- 
toxin— Antiyeast  serum  (Deutschmann  serum) — Antituberculosis  serum 
(Marmorek,  Maragliano,  etc.) — Related  Agents:  Plasma-serum  of 
Richet — Blister  serum — Pleural  fluid — Cerebrospinal  fluid—Joint  fluid — 
Proteins:  Egg  and  seralbumin— Milk— Fat-free  milk— Casein— Gelatin- 
Plant  proteins — Nucleo-proteins — Nucleo-hexyl — Protein  Split  Products: 
Proteoses  (Albumoses) — Deuteroalbumose — Globin — Histamine  Witte— 
Peptone — Enzymes :  Trypsin — Amylopsin — Leukoprotease — (Leukocytic 
Extract) — Tissue  Extracts:  Tumor  extracts  and  autolysates — Cartilage 
and  other  tissue  extracts  (Heilner) — Organotherapy — Vaccines:  Typhoid 
— Dysentery — Colon — Cholera — Meningococcus — Gonococcus — Staphylo- 
coccus  —  Streptococcus  —  Pyocyaneus  —  Pneumococcus  —  Influenza  and 
diphtheroid  vaccines — Mixed  vaccines — Vaccinurin,  Danysz  vaccine  and 
Much's  antigen — Bacterial  Extracts  and  Related  Substances:  Tubercu- 
lins!— Typhin — Coley's  fluid — Phylacogens — Bacterial  autolysates — Col- 
loidal Metals:  Gold — Silver — Platinum — Mercury — Sulphur — lodin — 
Zinc — Iron — Antimony — Manganese-^-Copper,  etc. — Miscellaneous:  Dis- 
tilled water — Hyper-  and  hypptonic  salt  solution — Sugar  solutions — 
Formalin — Solusin — Hetol — lodidea —  Turpentine  — Yeast —  Irradiation — 
Sunlight— Roentgen  rays— Radium  rays,  etc.— Biological  alterations- 
Depression  immunity. 

CHAPTER  III 
THE  NONSPECIFIC  REACTION ......      46 

Chill — Temperature— Pulse  rate — Blood  pressure — Sweating — Nausea  and 
vomiting — Splenic  enlargement — Effect  on  menstruation — Nervous  ir- 
ritability— Herpes  and  urticaria  headache — Delirium  glandular  activity 
—Nitrogen  balance— Effect  on  weight  curve— Renal  effects— Permea- 

xv 


xvi  TABLE  OF  CONTENTS 

PAGE 

bility  of  blood  sugar — Lymphagogue  effect — Leukocytes — Erythrocytes 
— Platelets  —  Blood  sugar  —  Fibrinogen  —  Thrombokinase  —  Serum  and 
lymph  enzymes — Protease  —  Peptidase  —  Lipase  —  Antif erment  —  Anti- 
bodies— Effect  on  the  Wassermann  reaction. 

CHAPTER  IV 
THE  FOCAL  REACTION 70 

The  question  of  specificity  of  Focal  Reactions — Classification  of  Focal  Re- 
actions— Activating  agents — Diphasic   character   of   Focal   Reactions — 
Mechanism  of  Focal  Reactions:    In  Vascularized  Foci — In   Avascular 
Foci  (Tuberculosis)— Therapeutic  application  of  the  Focal  Reaction. 


THEORIES 

CHAPTER  V 
THEORIES  CONCERNING  THE  MECHANISM  OF  THE  REACTION 83 

Weichardt's  theory  of  Plasma  activation— Selective  stimulation — Hyper- 
thermia — Nolfs  theory — Enzymes — Antibodies — Wright's  theory — The 
leukocytes — Cell  permeability  (Starkenstein). 

CHAPTER  VI 
THE  PROBABLE  MECHANISM  OF  THE  REACTION 99 

Protein  Intoxication  and  Detoxication — The  Mechanism  of  Recovery  in 
Pneumonia — The  Ferment-antif erment  balance  in  Pneumonia  and  in 
Tuberculosis — The  Reaction  in  Carcinoma — The  Effect  on  Local  In- 
flammation— The  Effects  of  the  Reaction  in  Localized  Lymphatic  Dis- 
ease (Typhoid) — The  Effects  of  the  Reaction  in  Localized  Lymphatic 
and  Interstitial  Disease  (Lobar  Pneumonia) — The  Effects  in  Generalized 
Infection  (Septicemia). 

CHAPTER  VII 
THE  RELATION  OF  THE  SKIN  TO  NONSPECIFIC  RESISTANCE 128 

Skin  Reactivity — Depression — Activation — Relation  to  Internal  Medicine — 
Esophylaxis — Heliotherapy — Mechanism  of  Recovery  in  the  Acute 
Exanthemata— Resistance  to  Syphilis. 


THE  CLINICAL  RESULTS 

CHAPTER  VIII 
ARTHRITIS     .    .    .    .    . >    s    s    >;    142 

Clinical  reports — Discussion — Safety — Effect  on  Endocarditis. 

CHAPTER  IX 
TYPHOID  FEVER .153 

Typhoid  vaccine  —  Intravenous  injections  —  Heterovaccines —  Albumoses  — 
Comparative  results — Milk  injections  and  other  procedures— Discussion 
— Mechanism  of  normal  recovery — Therapeutic  precautions — Para- 
typhoid fever. 


TABLE  OF  CONTENTS  xvii 

CHAPTER  X 

PAGE 

GONORRHEA  AND  ITS  COMPLICATIONS 170 

Culver's  report — Gonorrheal  arthritis — Other  complications— Local  injec- 
tions of  milk,  salt  solution,  iodides,  etc. — The  Provocative  Reaction — 
Adnexal  Inflammation. 

CHAPTER  XI 
INFECTIOUS  DISEASES 185 

Anthrax — Diphtheria  and  diphtheria  carriers — Dysentery  (Bacillary) — 
Erysipelas — Influenza  and  influenza!  pneumonia — Lethargic  encephalitis 
— Parotitis  and  orchitia— Pneumonia  (Lobar) — Puerperal  infections — 
Scarlet  Fever — Septicemia — Smallpox — Tetanus — Trench  Fever — Tuber- 
culosis— Typhus  Fever — Vincent's  Angina. 

CHAPTER  XII 
SPIROCHETAL  AND  PROTOZOAL  INFECTIONS 206 

Relapsing  Fever — Syphilis — Weil's  Disease — Malaria. 

CHAPTER  XIII 
MISCELLANEOUS  DISEASES 210 

Asthma — Angioneurotic  Edema — Anemia:  Secondary,  Pernicious — Hemor- 
rhagic  Diathesis — Nephritis— Pyelitis — Neuritis — Diseases  of  the  Ear — 
Neoplasms — Diseases  of  Children. 

CHAPTER  XIV 
THE  TREATMENT  OF  PARESIS,  TABES  AND  EPILEPSY    .........    224 

CHAPTER  XV 
DISEASES  OF  THE  SKIN >     .    230 

CHAPTER  XVI 
DISEASES  OF  THE  EYE ......    236 

CHAPTER  XVII 
INFLAMMATION        w    ......    242 

CHAPTER  XVIII 

INDICATIONS  AND  CONTRAINDICATIONS v    .    •7"""". .     .    247 

APPENDIX 
THE  PROTEINS  AND  THEIR  SPLIT  PRODUCTS 252 

(I)  The  Native  Proteins— Albumins — Globulins,  etc. — (II)  Conjugated  Pro- 
teins —  Chromoproteins  —  Glucoproteins  —  Phosphoproteins  (Casein) — 
Nucleoproteins,  Etc. — (III)  Derived  Proteins — (a)  Primary:  Proteins 
— Metaproteins— Coagulated  Proteins — (b)  Protein  Split  Products — 
Secondary  Derivatives— Proteoses  (Albumoses)— Peptones— Peptids— 
(c)  The  Amino  Acids. 


PROTEIN  THERAPY 

AND 

NONSPECIFIC  RESISTANCE 


PROTEIN  THERAPY 

CHAPTER  I 
THE  HISTORY  OF  PROTEIN  THERAPY 

The  remarkable  fact  that  some  individuals  are  resistant  to  infec- 
tious disease  while  others  are  not;  that  of  two  seemingly  equally  strong 
individuals,  the  one  may  die,  the  other  recover  from  the  same  in- 
fection, has  always  interested  biologists  and  physicians. 

Naturally  enough  the  efforts  to  explain  resistance  to  disease  have 
varied  with  the  mode  of  biological  thought  current  at  any  given  period. 
It  was  not  until  the  development  of  our  instruments  of  precision  made 
possible  the  work  of  Pasteur  and  of  Koch  that  the  study  of  the  causal 
relation  of  micro-organisms  to  certain  disease  processes  diverted  the 
interest  of  the  medical  mind  from  the  philosophic  tendency  that  had 
characterized  the  early  half  of  the  last  century,  to  the  concrete,  the 
direct,  the  specific  ideation  upon  which  modern  science  is  founded. 
Naturalistic  generalization  gave  place  to  accurate  biological  observa- 
tion. And  with  pathological  and  bacteriological  definition  of  disease 
processes,  the  mental  attitude  of  the  physician  likewise  changed  in 
regard  to  resistance  to  disease  as  a  general  phenomenon  to  inquiry 
regarding  resistance  to  specific  disease  processes. 

The  brilliant  era  of  specificity  in  therapeusis  that  was  ushered  in 
by  the  work  of  v.  Behring,  the  fascinating  serological  researches  of 
Ehrlich  and  of  Bordet,  the  discovery  of  the  specific  spirochaetecide  by 
Ehrlich  in  the  field  of  chemotherapy,  stamped  with  the  seal  of  success 
these  years  of  medical  advance — advance  made  wholly  on  a  back- 
ground of  the  strictest  specificity.  Naturally  enough  in  such  a  period 
of  successful  achievement,  minor  currents  passed  unnoticed.  Clinical 
observations  that  did  not  fit  in  with  the  prevailing  mode  of  thought 
were  but  half  heartedly  put  forward  and  soon  passed  into  oblivion. 
Wright  but  recently  pointed  out  a  few  such  instances  that  came  to 
his  attention  during  the  past  twenty  years: 

...  "I  confess  to  having  shared  the  conviction  that  immunization  is 
always  strictly  specific.  Twenty  years  ago,  when  it  was  alleged  before  the 
Indian  Plague  Commission,  that  antiplague  inoculation  had  cured  eczema, 
gonorrhea,  and  other  miscellaneous  infections,  I  thought  the  matter  unde- 

1 


2  PROTEIN  THERAPY 

serving  of  examination.  I  took  the  same  view  when  it  was  reported  in 
connection  with  antityphoid  inoculation  that  it  rendered  the  patients  much 
less  susceptible  to  malaria.  Again,  seven  years  ago,  when  applying  anti- 
pneumococcus  inoculation  as  a  preventive  against  pneumonia  in  the  Trans- 
vaal mines,  I  nourished  exactly  the  same  prejudices.  But  here  the  statis- 
tical results  which  were  obtained  in  the  Premier  Mine  demonstrated  that 
the  pneumococcus  inoculation  had,  in  addition  to  bringing  down  the  mor- 
tality from  pneumonia  by  85  per  cent.,  reduced  also  the  mortality  from 
other  diseases  by  50  per  cent.  From  that  on  we  had  to  take  up  into  our 
categories  the  fact  that  inoculation  produces  in  addition  to  'direct'  also 
'collateral'  immunization."  .  .  . 

Several  other  observations  must  be  recalled.  In  1893  Eugene 
Frankel  reported  on  the  treatment  of  some  57  cases  of  typhoid  fever 
treated  with  subcutaneous  injections  of  typhoid  bacilli.  The  results 
were  promising.  In  an  address  delivered  at  the  same  time  Rumpf  pre- 
sented a  similar  series  of  typhoid  patients,  but  treated  with  subcutane- 
ous injections  of  a  pyocyaneus  vaccine.  Rumpf  based  his  work  on 
the  experiments  of  Buchner  and  his  pupils  who  had  emphasized  that 
in  tuberculosis,  the  infection  then  under  most  intensive  study  in  Ger- 
many, not  only  tuberculin  but  other  bacterial  products  could  activate 
previously  latent  powers  of  resistance.  Romer,  working  along  the 
same  line,  had  found  that  tuberculous  animals  could  be  killed  by  ex- 
tracts obtained  from  pneumobacilli  and  bacillus  pyocyaneus  just  as 
well  as  with  tuberculin,  i.e.,  that  such  animals  were  susceptible  not 
only  to  a  specific  intoxication  because  of  some  abnormal  sensitiza- 
tion,  but  that  they  were  susceptible  to  other  toxic  products  as  well  be- 
cause of  their  infection.  Rumpf  concluded  that  while  soluble  toxins 
might  be  specific  and  call  forth  a  specific  response  on  the  part  of  the 
patient,  all  bacteria  probably  contained  a  common  component — non- 
specific— against  which  immunization  might  conceivably  be  carried 
out.  He  first  made  up  and  used  a  streptococcus  vaccine,  but  it  pos- 
sessed no  therapeutic  properties  so  far  as  typhoid  fever  was  concerned. 
It  was  then  that  he  made  up  his  pyocyaneus  vaccine  and  with  it 
achieved  results  that  in  many  ways  equalled  those  that  Frankel  had 
obtained  with  typhoid  vaccines.  In  his  series  of  30  cases  there  were 
two  deaths,  one  from  pneumonia,  the  other  from  perforation. 

Rumpf  observed  that  following  his  subcutaneous  injections  chills 
and  sweating  were  not  uncommon.  Usually  the  temperature  and  the 
pulse  began  to  come  down  within  two  days  after  commencing  the 
vaccines;  the  earlier  the  treatment  was  commenced  the  more  notice- 
able the  effect  on  the  clinical  course.  He  called  attention  in  par- 
ticular to  the  euphoria  that  was  observed  after  the  injection. 

This  paper,  published  at  a  time  that  witnessed  the  introduction  of 
diphtheria  and  tetanus  antitoxin,  was  practically  ignored;  the  more 
readily  when  several  competent  observers,  working  with  small  series 
of  cases  it  is  true,  could  not  confirm  Rumpf  s  results. 


THE  HISTORY  OF  PROTEIN  THERAPY  3 

Then  Horbaczewski  introduced  nucleins  and  found  that  lupus  vul- 
garis  reacted  with  a  typical  focal  reaction  to  the  nuclein,  that  is, 
the  nuclein  injection  caused  a  focal  reaction  about  the  lesion  just 
as  well  as  the  specific  substance.  Kiihne  next  analyzed  the  tuberculins 
and  noted  the  large  amount  of  protein  split  products  therein  contained. 
Koch  was  cognizant  of  the  fact  that  the  fever-producing  element  in 
the  tuberculins  was  not  part  of  the  specific  effect  which  he  was  seek- 
ing to  accentuate;  others  (such  as  Hueppe  and  Scholl)  insisted  that  it 
was  just  this  nonspecific  bacterial  protein  that  accounted  for  the 
entire  tuberculin  reaction.  As  a  result  particularly  of  Kiihne's  work, 
Matthes  and  Krehl  began  their  well-known  experiments  with  protein 
split  products  in  tuberculous  animals.  In  using  various  proteins  to 
bring  about  the  tuberculin  reaction  in  tuberculous  guinea  pigs  they 
found  among  others  that  milk  injections  would  also  activate  the  focus. 

In  this  work  Matthes  made  several  observations  that  have  a  di- 
rect bearing  on  the  problem  under  consideration.  He  noted  for  in- 
stance that  tuberculous  guinea  pigs  reacted  not  only  to  tuberculin 
with  the  well-known  temperature  rise,  but  to  injections  of  deutero- 
albumose  as  well.  With  small  doses  such  animals  responded  with  a 
typical  rise  in  temperature ;  large  doses  caused  a  fall  in  body  tempera- 
ture and  the  death  of  the  animal.  Nontuberculous  animals  would  at 
times  react  with  temperature  to  the  deuteroalbumose  injection,  but 
never  to  the  same  extent  as  infected  animals.  The  dosage  as  compared 
to  tuberculin  was  large,  nevertheless  the  results  caused  considerable 
doubt  in  his  own  mind  as  to  how  far  specificity  entered  into  the  tuber- 
culin reaction  and  interested  him  in  the  role  of  protein  split  products 
in  the  causation  of  fever. 

To  the  same  period  of  time  belongs  the  reintroduction  of  the  arti- 
ficial abscess  (the  fixation  abscess  of  Fochier),  a  therapeutic  pro- 
cedure related  to  the  seton  and  the  fontanelle.  Fochier  used  the  sterile 
abscess  (produced  by  injecting  turpentine)  in  puerperal  infections  with 
some  success.  The  method  was  in  vogue  for  a  number  of  years.  From 
Sahli's  clinic  Bauer  published  observations  on  a  series  of  cases  of 
pneumonia  treated  with  such  sterile  abscess  formation  (1  to  2  c.c.  of 
turpentine  being  injected  to  produce  the  abscess).  The  number  of 
cases  so  treated  was  too  small  to  be  of  any  particular  value  but  it  was 
noted  that  a  stimulation  of  leukocytes  was  always  brought  about  as 
a  result  of  the  injection. 

The  introduction  of  nucleic  acid  by  Horbaczewski  has  been  men- 
tioned. In  the  course  of  the  next  twenty  years  nucleic  acid  and  its 
salts  and  related  chemical  compounds  that  cause  a  leukocytic  reaction 
found  their  way  into  the  treatment  of  infectious  diseases.  Their  use 
was  advocated  because  it  was  assumed  that  their  action  consisted  in  a 
general  tissue  stimulation. 

Colloidal  metals,  especially  the  silver  preparations,  had  come  into 
use  after  their  introduction  by  Crede.  First  it  was  assumed  that  the 


4  PROTEIN  THERAPY 

silver  preparations  possessed  particular  streptococcicidal  properties 
and  they  were  consequently  injected  in  septic  conditions  due  to  strep- 
tococcus infections.  It  was  then  noticed  that  one  could  obtain  equally 
good  results  in  a  number  of  infections  due  to  other  organisms.  Finally 
the  colloidal  metals  have  come  to  be  recognized  as  purely  nonspecific 
reactive  agents. 

In  the  same  category  must  be  placed  a  rather  commonly  used 
procedure,  the  method  of  autoserotherapy  of  Gilbert.  Introduced  in 
1894  for  the  treatment  of  pleurisy  with  effusion  it  found  consider- 
able clinical  application.  The  technic  consisted  in  withdrawing  a 
small  amount  of  fluid  from  the  pleural  cavity  and  reinjecting  it  under 
the  skin.  At  times  a  slight  temperature  reaction  was  observed  follow- 
ing it.  Eisner  studied  the  reaction  in  experimental  animals  and  ob- 
served that  a  leukocytosis  usually  followed  the  injection;  to  this, 
and  to  the  general  constitutional  reaction  he  attributed  the  therapeutic 
benefit.  Zimmermann  had  also  noted  the  leukocytosis  which  he  had 
ascribed  to  the  stimulation  of  the  tissues  by  autolytic  products  that 
had  accumulated  in  the  pleural  exudate.  He  even  proceeded  to  show 
that  the  injection  of  peptone  would  produce  such  a  leukocytosis,  but 
did  not  continue  to  the  logical  conclusion  of  his  experiments.  Later 
the  method  of  autoserotherapy  was  extended,  particularly  in  the  field 
of  dermatology. 

In  tumor  treatment  we  have  had  two  related  measures.  These  have 
been  the  Beard  Trypsin  treatment  of  carcinoma  and  the  use  of  Coley's 
Fluid,  the  latter  used  especially  in  sarcoma.  Quite  apart  from  the 
theoretic  basis  that  was  put  forward  to  support  their  use  in  malignant 
disease,  it  is  to  be  noted  that  both  agents  were  followed  by  a  severe 
constitutional  reaction — chill,  fever,  increased  local  pain  and  evidence 
of  an  inflammatory  reaction,  followed  by  occasional  clinical  improve- 
ment, both  in  the  general  health  of  the  patient  and  the  arrest  of  the 
tumor  growth  for  a  period  of  time.  Whether  actual  cures  were  ever 
effected  is  for  the  present  study  unimportant;  both  reactions  were 
typical  nonspecific  phenomena  and  the  effect  on  the  local  process  just 
what  would  be  anticipated  under  the  circumstances. 

A  method  closely  related  to  these  is  that  of  the  injection  of  tumor 
autoly sates.  These  are  injected  either  intramuscularly  or  intrave- 
nously in  small  doses  and  are  almost  invariably  followed  by  evidences 
of  a  general  reaction  on  the  part  of  the  patient  (Funkenbein,  Blumen- 
thal)  as  well  as  by  changes  in  the  nitrogen  balance  (Bauer,  Latzel  and 
Wessely) . 

Another  nonspecific  method  and  one  that  has  at  times  been  fol- 
lowed by  very  favorable  clinical  results  has  been  that  of  the  injection 
of  leukocytic  extracts  in  patients  ill  from  a  variety  of  infectious  dis- 
eases. Petterson  had  observed  that  in  animals  such  injections  seemed 
to  have  a  very  decided  protective  effect  against  infection,  and  Opie, 
too,  had  made  similar  observations.  In  1908  Hiss  and  Zinsser  began 


THE  HISTORY  OF  PROTEIN  THERAPY  5 

to  use  such  an  extract  in  patients.  They  were  not  able  at  the  time 
to  account  definitely  for  the  therapeutic  effect  obtained  but  Zinsser 
has  since  expressed  the  opinion  that  the  results  were  probably  to  be 
accounted  for  on  the  basis  of  a  nonspecific  reaction. 

Occasional  clinical  reports  were  made  during  the  period  between 
1890  and  1910  which  detailed  success  in  infectious  diseases  through 
a  number  of  therapeutic  measures  purely  nonspecific  in  character, 
among  them  those  of  Paton,  who  used  normal  serum  and  diphtheria 
antitoxin  in  the  treatment  of  tuberculosis,  arthritis,  and  cerebrospinal 
meningitis. 

Paton's  work  was  based  on  preceding  observations  made  by  De 
Minicis,  who  had  treated  a  small  series  of  diphtheria  cases  with  diph- 
theria antitoxin  per  os,  and  on  those  of  Lilienthal  and  of  McCallum, 
who  had  reported  that  diphtheria  antitoxin  possessed  curative  prop- 
erties when  given  in  a  variety  of  infections  such  as  sepsis,  tuberculosis, 
adnexal  inflammatory  conditions,  lupus,  etc.  Paton  published  a  small 
volume  detailing  his  clinical  experience  with  the  use  of  diphtheria 
antitoxin  given  by  mouth ;  he  found  that  not  only  normal  horse  serum 
but  sheep  serum  and  ox  serum  possessed  the  stimulating  qualities 
to  which  he  attributed  the  therapeutic  effects.  This  paraspecific  sero- 
therapy has  been  used  extensively  in  France. 

Darier  has  collected  some  of  the  clinical  literature  concerned  with 
the  reaction  and  more  recently  Cumston  has  discussed  it.  That  the 
injection  of  diphtheria  antitoxin  might  at  times  produce  a  transient 
increase  in  the  temperature  of  the  patient  had  been  observed  very 
early  by  Ewing,  who  also  noted  the  leukocytic  response  after  injections, 
that  is,  a  primary  leukopenia  lasting  for  about  one-half  hour,  fol- 
lowed by  a  leukocytosis.  The  use  of  normal  horse  serum  in  the  treat- 
ment of  certain  alterations  of  the  coagulation  balance  of  the  blood  has 
also  become  quite  common  in  recent  years  (Weil)  and  inoculation  of 
the  patients  serum,  plasma  or  whole  blood,  either  subcutaneously  or 
intravenously — autoserotherapy  as  it  is  termed — has  been  practiced 
especially  by  the  dermatologists.  Within  the  past  five  years  some 
success  has  been  reported  in  this  limited  field  but  the  method  was  never 
recognized  as  being  part  and  parcel  of  a  general  reaction. 

In  1917  Deutschmann,  seeking  to  find  a  method  of  treatment  for 
certain  eye  diseases  against  which  remedial  measures  were  unsat- 
isfactory, began  the  immunization  of  horses  with  yeast  cells  and  used 
the  serum  for  the  treatment  of  a  variety  of  infectious  diseases.  Yeast 
has  for  many  years  been  supposed  to  augment  the  resisting  powers 
of  the  body  when  given  by  mouth;  yeast  extract  has  also  been  given 
subcutaneously  for  the  same  purposes  and  has  also  been  applied  in 
the  treatment  of  malignant  diseases  (especially  by  Italian  clinicians 
on  the  basis  of  the  work  of  Sanfelice).  When  so  injected  the  effect 
is  probably  due  to  the  nuclein  content  of  the  extract. 

In  Deutschmann's  work  about  2  c.c.  of  the  serum  was  injected 


6  PROTEIN  THERAPY 

and  this  was  followed  by  the  usual  nonspecific  reaction — a  slight  rise 
in  temperature,  pronounced  euphoria,  occasional  crisis  in  acute 
infectious  disease,  etc. 

In  America  we  had,  however,  one  treatment  that  received  con- 
siderable unfavorable  notoriety,  a  nonspecific  method  in  its  effects, 
although  introduced  on  a  different  basis.  In  1911  Schafer  reported 
the  therapeutic  use  of  a  bacterial  product  with  which  he  had  obtained 
remarkable  recoveries  in  certain  infectious  diseases. 

This  work  was  done  at  a  time  when  the  subject  of  mixed  infec- 
tions was  prominently  under  discussion  as  an  etiological  factor  in  dis- 
ease development.  Schafer  formulated  a  theory  of  immunization  to 
fit  the  successful  use  of  his  mixed  vaccine.  This  was  that  in  treat- 
ing a  disease,  one  had  not  only  to  consider  the  specific  exciting  organ- 
ism in  the  vaccine,  but  that  the  secondary  invaders — the  heterogeneous 
group  of  semisaprophytic  and  saprophytic  bacteria  that  were  in  sym- 
biotic relation  with  the  original  invader — had  to  be  considered  in  the 
vaccine  as  well. 

Schafer  demonstrated  his  vaccine  mixture  in  several  hospitals, 
treating  chiefly  arthritic  cases.  The  injection,  usually  made  intrave- 
nously because  subcutaneous  injections  were  very  painful,  was  always 
followed  by  a  severe  general  reaction,  no  matter  whether  the  thera- 
peutic result  was  good  or  bad.  In  some  cases  the  success  following 
the  single  injection  was  remarkable;  in  others,  merely  the  memory 
of  the  very  unpleasant  chill  and  fever — "the  Ordeal  by  Chill  and 
Fire"  as  one  facetious  patient  expressed  it — remained,  with  no  thera- 
peutic benefit.  The  selfsame  vaccine  in  one  case  cured  arthritis, 
in  another  a  catarrhal  jaundice,  in  another  a  neuralgia.  At  this 
time  a  pharmaceutical  house  purchased  Schafer's  formula  and  began 
a  country-wide  exploitation  of  the  same,  using  a  trade  name  for  the 
product.  The  entire  campaign,  naturally  enough,  met  with  decided 
disapproval  on  the  part  of  the  medical  profession,  not  only  because  of 
the  proprietary  nature  of  the  product  and  the  blatant  commercial 
method  of  its  introduction,  but  because  of  the  lack  of  scientific  or 
laboratory  study  that  was  evident  from  the  very  beginning. 

Herescu  and  Strominger  attacked  the  problem  from  a  different 
position.  Noting  the  morphological  similarity  that  exists  between  the 
gonococcus  and  the  meningococcus,  they  began  using  antimeningococ- 
cus  serum  in  the  treatment  of  gonorrheal  arthritis,  gonorrheal 
ophthalmia,  septicemia,  and  other  gonorrheal  complications,  with  con- 
siderable success. 

The  use  of  mixed  gonococcus  vaccines  had  become  quite  common 
both  in  France  and  in  Germany  and  in  their  clinical  application 
a  number  of  observers  began  to  use  them  intravenously  in  relatively 
large  doses.  In  the  gonorrheal  complications  (and  in  iritis  of  non- 
gonorrheal  origin — Kreibich)  it  was  found  that  this  form  of  injection 
was  frequently  satisfactory.  Brasch,  who  studied  the  general  re- 


THE  HISTORY  OF  PROTEIN  THERAPY  7 

action  that  followed  the  injections,  noted  in  particular  the  typical 
effect  on  the  leukocytic  picture. 

We  have  then  a  whole  list  of  agents  and  methods  that  have  been 
employed,  some  empirically,  others  with  a  definite  immunological 
theory  underlying  their  use,  but  all,  whether  bacteriological  product, 
or  enzyme,  or  chemical,  producing  a  more  or  less  marked  constitutional 
reaction  on  the  part  of  the  patient.  It  is  curious  that  this  common 
feature  was  not  emphasized  or  even  recognized  as  a  possible  part  of 
the  therapeutic  mechanism. 

Throughout  the  period  under  discussion,  when  these  various  meth- 
ods and  substances  were  being  introduced,  vaccinotherapy  as  ad- 
vocated by  Wright  was  being  tried  out  in  practically  every  form  of 
infection;  not  always  with  success  but  with  sufficient  result  to  keep 
the  method  in  use  in  medical  practice. 

When  failure  resulted  there  were,  as  a  rule,  extenuating  circum- 
stances upon  which  to  throw  the  blame.  At  first  it  had  been  the 
practice  to  use  as  a  vaccine  an  organism  of  the  type  known  to  cause  the 
particular  infection  with  which  we  were  dealing.  Then  when  results 
were  not  forthcoming,  effort  was  made  to  isolate  the  particular  organ- 
ism causing  the  infection  in  order  to  produce  an  autogenous  vac- 
cine. This  failing,  we  had  the  consolation  that  we  probably  had  not 
succeeded  in  isolating  the  particular  strain  that  had  caused  the  in- 
fection. 

On  the  basis  of  his  opsonic  work  Wright  had  differentiated  a 
negative  and  a  positive  phase  of  resistance  following  the  vaccine  in- 
jection. The  dread  of  the  negative  phase  was  sufficiently  impressed 
on  every  immunologist  to  prevent  the  use  of  large  doses  of  vaccine 
or  such  that  would  lead  to  a  general  reaction  on  the  part  of  the  pa- 
tient. Indeed,  ever  since  the  time  of  Koch's  work  with  tuberculin, 
when  overzealous  workers  using  large  doses  of  tuberculin  had  often 
done  irreparable  damage  by  breaking  down  the  normal  connective 
tissue  defense  of  the  patient,  immunologists  had  used  great  care 
in  avoiding  general  systemic  reactions. 

When  vaccines  were  carefully  used  there  was  no  doubt  that  the 
patient  gave  evidence  of  increased  antibody  production,  measured 
both  by  the  opsonic  index,  the  agglutinin  titer  and  the  method  of 
complement  deviation,  but  here  again  the  therapeutic  result  did  not 
measure  up  to  the  expectation.  Immune  bodies  might  be  stimulated 
to  a  sufficient  degree  but  the  patient  was  not  cured. 

The  modern  conception  of  protein  therapy  and  nonspecific  re- 
sistance was  a  direct  development,  however,  of  this  work  with  vac- 
cines. In  typhoid  fever  the  therapeutic  use  of  vaccines,  either  made 
up  of  killed  but  otherwise  unaltered  organisms,  or  of  bacteria  altered 
in  a  number  of  ways,  had  been  given  rather  extended  use  and  with 
fair  clinical  results.  In  the  decade  following  the  year  1906,  the  bacteri- 
otherapy  of  typhoid  began  to  be  a  recognized  procedure.  The  dura- 


8  PROTEIN  THERAPY 

tion  of  thei  disease  was  undoubtedly  shortened  thereby  and  the 
mortality  lowered,  but  the  difference  between  the  treated  and  the  un- 
treated cases  was  seldom  striking  enough  to  popularize  the  method 
among  the  general  profession.  Then  it  was  that  in  Argentine  a  group 
of  physicians  began  the  intravenous  use  of  typhoid  vaccine.  Penna, 
Tores,  Dessy,  Grafinola,  Fossati,  and  others  thereby  obtained  quite 
remarkable  results,  the  disease  in  some  cases  being  aborted  almost  at 
its  inception,  in  others  terminated  by  crisis,  in  others  by  lysis  shortly 
after  the  injection. 

Kraus,  who  was  working  in  Argentine,  heard  of  these  results  and 
after  observing  the  effects  investigated  whether  other  organisms  would 
not  produce  the  same  results  when  so  injected.  He  found  this  to 
be  true  with  colon  vaccine. 

Quite  independently  Ichikawa  had  reported  on  the  advantage  of 
the  intravenous  injection  of  typhoid  vaccine  at  a  meeting  of  the 
Medical  Society  of  Osaka  in  April,  1912,  and  in  1914  reported  his 
results  with  87  cases  of  typhoid  treated  with  a  sensitized  vaccine. 
The  normal  mortality  in  his  untreated  cases  was  over  30%;  when 
treated  with  the  vaccine  intravenously  the  mortality  sank  to  11% 
and  in  more  than  half  the  cases  the  disease  was  terminated  after 
the  first  or  second  injection.  Ichikawa  made  the  further  interesting 
observation  that  when  he  treated  paratyphoid  fever  with  the  same 
typhoid  vaccine,  he  obtained  equally  good  results,  i.e.,  the  result 
was  not  due  to  a  strictly  specific  reaction.  Ichikawa  found  that 
following  the  typhoid  injections  in  the  paratyphoid  patients,  the  spe- 
cific paratyphoid  antibodies  were  mobilized. 

Some  hemorrhages  were  noted  after  the  injections,  although  the 
author  considered  them  less  frequent  in  the  vaccinated  group  than  in 
the  unvaccinated.  Heart  disease  and  pregnancy  he  naturally  con- 
sidered contraindications  to  the  therapeutic  injections  because  of  the 
pronounced  reaction  that  followed  the  administration  of  intravenous 
therapy. 

We  had  then  two  reports  of  heterobacteriotherapy  that  had  yielded 
startling  clinical  results — typhoid  treated  with  colon  bacilli  and  para- 
typhoid treated  with  typhoid  vaccine — clinical  results  that  could  not 
well  be  denied,  although  the  immunologist  might  still  allege  that  we 
were  dealing  with  a  group  reaction,  rather  than  a  true  heterobacterial 
vaccine  effect. 

Kraus,  however,  definitely  settled  this  point  when  he  reported 
favorable  results  in  puerperal  infection  treated  with  colon  vaccine 
and  with  this  as  a  basis  began  the  treatment  of  scarlet  fever,  plague 
and  septicemia. 

A  predecessor  of  Kraus  and  perhaps  the  first  observer  who  clearly 
pointed  out  the  value  of  heterobacteriotherapy  was  Renaud  (1911). 
He  had  been  working  with  typhoid  vaccine  killed  by  quartz  light  radi- 
ation and  noted  that  the  injection  of  such  vaccine  had  a  definite 


THE  HISTORY  OF  PROTEIN  THERAPY  9 

therapeutic  effect  on  a  number  of  inflammatory  conditions  of  non- 
typhoidal  origin. 

Clinical  results  such  as  those  reported  by  Renaud,  by  Kraus  and 
by  Ichikawa  were  not  to  be  explained  away  as  due  to  accident.  The 
conception  of  strict  specificity  in  therapeusis  that  had  been  built  up 
in  the  laboratory  had  to  give  way  before  a  clinical  demonstration  that 
could  no  longer  be  ignored.  Our  recognition  of  nonspecific  therapy 
really  had  its  inception  with  these  three  papers.  Nor  was  it  long 
before  a  series  of  corroborative  observations  appeared  in  the  European 
literature  from  a  number  of  clinics  and  in  a  number  of  diseases.  Many 
clinical  phenomena  heretofore  obscure  and  never  satisfactorily  ac- 
counted for  on  our  older  conception  of  immunity  began  to  appear 
relatively  simple  and  understandable  when  studied  from  the  new 
point  of  view. 

From  heterobacteriotherapy  it  was  but  a  logical  step  to  attempt 
the  intravenous  injection  of  bacterial  components  and  bacterial  split 
products,  then  to  protein  split  products  of  nonbacterial  origin  and 
finally  to  the  realization  that  any  substance  which  was  capable  of 
inducing  the  shock  reaction  on  the  part  of  the  patient  would  result 
in  general  in  the  same  therapeutic  change.  We  were  dealing  with  an 
ergotropie  as  von  Groer  termed  the  reaction — "eine  Umstimmung" — 
of  the  whole  organism  (analogous  to  our  term  desensitization)  which 
made  it  resistant  to  intoxication.  Soon  a  number  of  agents  were  so 
used.  Schmidt  and  Saxl  introduced  milk  injections,  Liidke  the  in- 
jection of  proteoses  or  albumoses,  Mittlander  the  use  of  hypertonic 
salt  solution.  Distilled  water  and  foreign  sera  were  next  added 
and  recently  the  ancient  method  of  producing  sterile  abscesses — by 
injecting  minute  doses  of  turpentine  and  hypertonic  salt  solution — has 
been  revived. 

It  was  recognized,  too,  that  some  of  the  older  substances,  such 
as  nucleic  acid,  colloidal  metals,  enzymes,  lipoids  and  a  long  list  of 
substances,  the  therapeutic  effect  of  which  had  been  variously  ex- 
plained, all  belonged  in  the  same  category.  When  reviewed  from 
this  point  of  view  it  became  evident  that  they  all  brought  about  a 
general  reaction  which  manifested  itself  as  a  rule  in  the  chill,  the 
fever  and  the  leukocytosis,  and  those  which  were  most  successful 
clinically  were  the  ones  following  the  use  of  which  the  reaction  was 
greatest.  It  had  also  been  the  common  experience  with  the  entire 
group  that  in  order  to  be  effective  they  had  to  be  given  early  in  the 
disease ;  when  used  late  the  effect  was  much  less  certain. 

In  view  of  the  undeniably  striking  therapeutic  results  at  times 
achieved  with  nonspecific  therapy  certain  enthusiastic  workers  im- 
mediately went  to  the  extreme  view  that  specificity  was  valueless 
in  therapeusis  and  were  ready  to  throw  overboard  the  accumulated 
results  of  the  past  thirty  years.  And  the  best  known  and  most  widely 
used  of  our  specific  agents,  diphtheria  antitoxin,  was  the  one  that  was 


10  PROTEIN  THERAPY 

first  brought  into  question.  Bingel  treated  about  1,000  cases  of  diph- 
theria, one-half  of  the  group  with  the  specific  antitoxin,  the  other 
half  with  "empty,"  i.e.,  normal  horse  serum.  According  to  his  report 
the  clinical  results  were  equally  satisfactory  in  both  series.  Subse- 
quently a  number  of  German  clinicians  went  over  his  results  but  could 
not  confirm  them  to  the  extent  that  Bingel  had  claimed.  One  point 
of  value  was,  however,  brought  to  our  attention  by  this  discussion 
of  the  antitoxin  question.  Along  with  the  specific  antitoxin  value 
the  serum  contained  a  nonspecific  stimulating  element  in  the  horse 
serum  protein.  Our  modern  highly  concentrated  sera  naturally  have 
lost  this  nonspecific  factor  to  a  considerable  degree  in  the  process  of 
concentration,  thus  justifying  the  criticism  that  has  repeatedly  found 
expression  in  recent  years,  that  the  modern  concentrated  serum  did 
not  seem  so  effective,  all  things  considered,  as  the  old  serum  which 
was  not  so  high  in  antitoxin  units.  Concentrated  antitoxin  contains 
less  of  the  nonspecific  factor;  whatever  may  have  been  the  clinical 
value  of  this  element  has  been  lost  in  the  modern  preparations. 
(Meyer.) 

This  recognition  of  dualism  in  the  therapeutic  effect,  the  specific 
antitoxic  factor  and  the  nonspecific  stimulating  factor  of  the  diph- 
theria antitoxin  merely  illustrates  the  importance  of  the  unbiased  study 
of  all  factors  in  therapy. 

We  are  fairly  well  grounded  in  our  knowledge  of  the  specific  factors 
of  immunity.  Our  knowledge  of  the  nonspecific  elements  is  still  de- 
cidedly fragmentary.  Enthusiasm  in  one  direction  should  not  for 
an  instant  obscure  our  vision  of  all  other  possible  factors  in  resistance. 

Here  in  America  interest  in  this  particular  phase  of  resistance 
was  stimulated  by  the  work  of  Vaughan  and  Wheeler,  of  Opie  and 
his  associates  and  later  by  that  of  Jobling  and  his  co-workers. 

During  the  course  of  these  latter  studies  we  had  under  observa- 
tion a  series  of  animals  intoxicated  with  a  variety  of  bacterial  and 
other  protein  substances  and  noted  in  these  animals  a  marked  mobili- 
zation of  serum  enzymes.  When  we  became  familiar  with  the  work 
of  Kraus  and  Ichikawa  we  studied  the  problem  from  the  point  of 
view  of  its  practical  application  and  concluded  that  at  least  part  of 
the  therapeutic  effect  must  be  due  to  enzyme  action.  Inasmuch  as  we 
had  previously  found  that  other  agents  besides  bacterial  vaccines 
would  produce  precisely  the  same  enzyme  mobilization  we  concluded  to 
try  a  series  of  protein  split  products  in  patients  ill  with  typhoid  fever. 
While  this  work  was  under  way  an  identical  investigation  carried  out 
by  Liidke  with  albumoses  came  to  our  knowledge,  delayed  of  course  by 
the  exigencies  of  the  war.  Miller  and  Lusk  had  in  the  meantime  also 
become  interested  in  this  form  of  therapy  and  were  the  first  in  this 
country  to  report  a  larger  series  of  cases  so  treated.  They  used  both 
typhoid  vaccine  and  secondary  proteoses  in  their  work.  Smith  in  a 
paper  published  at  the  same  time  reported  on  the  therapeutic  bene- 


THE  HISTORY  OF  PROTEIN  THERAPY  11 

fit  of  the  anaphylactic  shock  reaction  in  patients  suffering  from  gon- 
orrheal  complications. 

The  publication  of  these  papers  directed  the  attention  of  the 
American  profession  to  this  form  of  therapy  and  there  have  since 
appeared  a  number  of  reports  dealing  with  nonspecific  therapy  in  a 
variety  of  diseases.  These  will  be  discussed  in  detail. 


CHAPTER  II 
THE  NONSPECIFIC  AGENTS 

In  the  practice  of  nonspecific  therapy  a  large  number  of  therapeutic 
agents  have  been  used,  varying  from  the  ancient  forms  of  counter- 
irritation  to  our  present  methods  of  heterobacteriotherapy,  of  protein 
therapy  and  of  the  intravenous  injection  of  colloidal  metals  or  other 
colloidal  substances.  In  discussing  these  various  agents  that  we  have 
at  our  disposal  to  induce  the  "plasmaactivation"  or  the  "ergotropie" 
as  one  may  choose  to  term  the  reaction,  it  will  be  of  some  interest 
to  include  a  number  because  of  their  historic  association  or  because 
of  their  theoretic  rather  than  their  practical  therapeutic  value.  Their 
inclusion  is  therefore  not  to  be  regarded  as  an  endorsement  of  their 
usefulness  in  therapeusis  nor  as  an  advocacy  for  their  employment 
in  practice.  They  are  gathered  together  under  a  single  group  be- 
cause it  seems  most  probable  that  their  occasional  utility — and  of 
this  there  can  be  no  question  in  some  instances — seems  based  on  a 
similar  reaction  that  they  bring  about  in  the  body,  i.e.,  true  tissue 
stimulation  and  activation,  exercising  their  therapeutic  power  by  alter- 
ing the  reactivity  of  the  whole  organism,  rather  than  influencing  di- 
rectly the  cause  of  the  pathological  process.  The  following  list,  ex- 
tensive though  it  is,  is  by  no  means  complete.  The  various  drugs  that 
possibly  are  useful  because  of  a  similar  stimulation — among  them  some 
of  the  mercury  preparations;  cinnamic  and  succinic  acids  and  their 
salts,  formic  acid,  quinin,  the  antipyretics,  iodin,  etc., — have  not  been 
included  because  it  would  lead  the  discussion  too  far  afield.  A  large 
number  of  other  and  older  methods  that  at  some  time  in  history  have 
been  used  in  medicine  and  which  probably  had  as  the  basis  of  their 
usefulness  the  same  general  reaction,  have  also  been  omitted  be- 
cause a  discussion  of  them,  other  than  emphasizing  the  historical  con- 
tinuity of  their  employment  as  nonspecific  agents  in  therapeusis,  would 
have  no  value. 

THE  NONSPECIFIC  AGENTS 

COUNTERIRRITANTS 

Cautery          Seton          Fontanelle          Moxa          Blister          Rubefacient 

BLOOD  AND  SERUMS 

Normal — Human,  Horse,  Sheep,  Beef,  Goat,  Chicken,  etc. 
Immune — Human  Convalescent  Serum;  Antimeningococcus  Serum,  Anti- 
dysentery  Serum,  Antistreptococcus  Serum. 
12 


THE  NONSPECIFIC  AGENTS  13 

Diphtheria  and  Tetanus  Antitoxin. 
Antiyeast  Serum  (Deutschmann  Serum). 
Tuberculosis  Serum  (Marmorek,  Maragliano,  etc.). 

Related  Agents— Plasma  Serum  (Richet),  Blister  Serum,  Pleural  Fluid, 
Cerebrospinal  Fluid. 

PROTEINS 
Egg  Albumin  and  Seralbumin      Milk      Fat-free  Milk      Casein      Gelatin 

Plant  Proteins — Nucleoproteins — Nucleohexyl 

Protein  Split  Products 
Proteoses        Deutero-albumose        Histamin        Globin        Witte  Peptone 

Enzymes 
Trypsin  Amylopsin  Leukoprotease  (Leukocytic  Extracts) 

Tissue  Extracts 

Tumor  Autolysates  and  Extracts  Cartilage  and  Vascular  Extracts 

(Heilner) 

Organotherapy 

Vaccines 

Typhoid,  Dysentery,  Colon  and  Cholera  Vaccines.  Meningococcus  and 
Gonococcus  Vaccines.  Staphylococcus,  Streptococcus,  Pyocyaneus 
and  Pneumococcus  Vaccines.  Influenza,  and  Diphtheroid  Vac- 
cines, etc. 

Mixed  Vaccines — Vaccinurin.    Danysz'  Method.    Muchjs  Antigen. 

BACTERIAL  EXTRACTS  AND  RELATED  PRODUCTS 
Tuberculins     Typhin     Coley's  Fluid     Phylacogens     Bacterial  Autolysates 

COLLOIDAL  METALS 
Gold     Silver     Manganese     Platinum     Sulphur     Mercury     Zinc     Iron 

MISCELLANEOUS 

Hypertonic  and  Hypotonic  Salt  Solutions    Sugar  Solutions    Distilled)Water 
Formalin     Solusin     Hetol     lodids     Turpentine     Antipyretics 

Yeasts 

Irradiation — Sunlight      Roentgen  Rays      Radium 
Biological  Alterations  Depression  Immunity 


14  PROTEIN  THERAPY 

COUNTERIRRITATION 
(Thermocautery ,  Seton,  Fontanelle,  Moxa,  Blisters,  Rubefacients) 

These,  perhaps  the  most  ancient  of  our  methods  of  intervention  in 
disease  processes,  purely  empirical  in  origin,  represent  undoubtedly  a 
form  of  nonspecific  therapy.  Crude  and  barbarous  in  their  applica- 
tion though  some  were,  there  can  be  little  doubt  as  to  their  occasional 
efficacy.  Their  very  antiquity,  their  widespread  use  among  all  peoples 
and  their  long  continuance  in  practice  more  than  warrant  this  as- 
sumption. And  their  supposed  effects  on  inflammation — the  accelera- 
tion of  repair — relief  from  pain — hastening  of  absorption  of  exudates, 
might  be  expected  to  follow  as  a  result  of  nonspecific  protein  therapy 
as  we  now  understand  it. 

Every  one  of  these  procedures  has  as  its  basis  the  production  of 
a  focus  either  of  necrosis — such  as  produced  by  the  cautery;  of  sup- 
puration— as  with  the  use  of  the  seton  or  the  fontanelle;  or  in  the 
milder  forms  the  production  of  an  area  of  exudation,  inflammatory 
in  character,  usually  serous  or  seropurulent.  The  absorption  of  these 
pathological  exudates  by  the  body  must  lead  to  a  tissue  stimulation — 
perhaps  milder  in  degree  and  longer  in  duration — similar  to  that  which 
follows  in  the  wake  of  our  more  modern  nonspecific  therapeutic  in- 
jection. Bloch  was  one  of  the  first  to  call  attention  to  the  fact  that 
our  nonspecific  therapy  is  but  part  and  parcel  of  this  older  practice 
of  counterirritation. 

While  counterirritation  was,  as  a  rule,  limited  in  its  applica- 
tion to  localized  inflammation  and  seldom  if  ever  used  in  acute 
infectious  diseases,  we  do  find  that  it  was  recommended  in  inflamma- 
tory rheumatism,  curiously  enough  the  one  disease  in  which  modern 
nonspecific  therapy  has  perhaps  been  most  consistently  successful. 

The  Actual  Cautery  was  considered  the  most  effectual  agent.  We 
now  know  that  following  a  burn  the  resorption  of  necrotic  material 
from  the  burned  area  may  result  in  a  typical  protein  shock  reaction, 
either  acute  or  protracted,  depending  of  course  on  the  degree  and  the 
area  of  injury.  Pfeiffer  has  recently  studied  in  detail  the  flooding 
of  the  organism  with  proteolytic  enzymes  following  both  burns  and 
evitable  infection  of  such  issues. 

The  Seton,  the  Fontanelle,  and  Moxa  were  all  methods  designed  to 
produce  a  superficial  suppuration  over  a  longer  period  of  time.  Not 
only  were  necrotic  tissue  products  being  absorbed  from  such  foci,  but 
a  heterovaccination  carried  out  at  the  same  time  because  of  the  in- 
evitable infection  of  such  tissues. 

The  milder  methods  produced  merely  local  irritation  of  the  skin 
either  with  vesication  or  hyperemia;  absorption  of  a  slight  inflam- 
matory exudate  might  take  place  from  both.  In  all  of  these  pro- 


THE  NONSPECIFIC  AGENTS  15 

cedures,  differing  but  in  degree,  we  have  the  elements  of  the  modern 
nonspecific  therapy,  the  absorption  of  a  foreign  protein  (disintegrat- 
ing autogenous  material — either  burned  tissue,  disintegrating  leuko- 
cytes, fibrin  or  serum  from  an  exudate) — the  reaction  of  the  body  to 
this  material  with  increased  activity;  stimulation  of  the  bone  marrow; 
mobilization  of  leukocytes,  of  enzymes;  the  lessening  of  the  nervous 
irritability,  etc. 

Counterirritation  was,  however,  limited  in  its  application  to  lo- 
calized inflammatory  conditions,  differing  in  so  far  from  the  applica- 
tion of  the  nonspecific  methods  at  present  in  vogue. 

Calleja  has  but  recently  devised  a  method  of  therapy  which  he  considers 
an  immunization  against  necrosis  based  essentially  on  these  older  methods. 
Calleja  assumes  that  the  derivatives  of  empiric  medicine,  the  blisters,  the 
fixation  abscess,  etc.,  owe  their  efficacy  to  the  fact  that  they  induce  an 
active  and  a  passive  immunization  against  the  effects  of  the  necrosis  of 
the  tissues  in  the  disease  process.  Subcutaneous  injection  of  3  or  4  drops 
of  chloroform  at  different  points,  to  a  total  of  from  3  to  5  c.c.,  is  a  con- 
venient method  of  this  "causticotherapy,"  and  he  supplements  it  with  horse 
serum  prepared  like  diphtheria  antitoxin,  only  using  instead  of  diphtheria 
bacilli,  human  tissue  scraps  rendered  necrotic  with  chloroform. 

The  term  "counterirritation"  and  the  theories  advanced  to  ex- 
plain the  therapeutic  measure  in  the  treatment  of  disease  have  gone 
out  of  fashion,  together  with  the  agents  that  were  used  for  many 
years.  At  times  and  under  certain  undetermined  conditions  results 
were  achieved  by  means  of  counterirritant  measures  that  were  quite 
satisfactory.  But  counterirritation  was  a  therapeutic  measure  abso- 
lutely empirical  in  character  and  the  fact  that  no  possible  theory  of 
modern  medicine  could  account  for  its  potential  benefit  was  perhaps 
one  of  the  reasons  that  modern  medicine  discarded  the  practice.  As 
Gillies  has  expressed  it,  "The  remedy,  or  let  us  say  mode  of  treat- 
ment, fell  into  disrepute  not  because  it  failed  as  a  remedy  or  as  a  mode 
of  treatment,  but  for  the  very  peculiar  reason  that  we  do  not  under- 
stand and  cannot  explain  how  it  succeeds,  for  it  is  allowed  that  not 
infrequently  it  does  succeed."  Curiously  enough  we  continued  to 
elaborate  procedures  that  were  obviously  similar  to  counterirritation 
both  in  character  and  in  their  therapeutic  object,  but  under  a  variety 
of  new  names  and  based  on  modern  scientific  theories  of  immunity. 
So,  for  instance,  the  autoserotherapy  used  in  pleural  exudates  whereby 
a  small  amount  of  the  pleural  exudate  is  withdrawn  and  reinjected 
under  the  skin  of  the  patient,  in  mechanism  analogous  to  the  older 
form  of  vesication. 

It  was  not,  however,  until  within  the  last  few  years  that  the  pos- 
sibility was  suggested  by  observers  interested  in  nonspecific  therapy 
that  the  same  mechanism  that  was  concerned  in  the  one  was  possibly 
involved  in  the  other;  Luithlen  has  even  ascribed  the  possible  thera- 


16  PROTEIN  THERAPY 

peutic  effects  of  repeated  bloodletting  to  biological  alterations  related 
to  protein  therapy. 

BLOOD,  SERUMS  AND  RELATED  AGENTS 

Blood  Transfusion. — One  of  the  very  early  methods  of  nonspecific 
therapy  involved  the  transfusion  of  whole  blood  from  human  or  animal 
sources;  with  the  method  a  reaction  on  the  part  of  the  patient  was  a 
common  observation.  It  was  this  reaction  that  made  the  method 
dangerous,  because  it  could  not  be  controlled  and  yet  it  seems  to  have 
been  recognized  that  in  its  occurrence  lay  the  usefulness  of  the  method 
as  a  therapeutic  measure.  Hasse  used  sheep's  blood  in  the  treatment 
of  a  large  number  of  diseases  (1874)  and  Eckert  (1876)  definitely  rec- 
ognized that  the  injected  or  transfused  blood  did  not  act  as  a  substitute 
but  as  a  chemical  irritant  for  the  organism  which  had  received  the 
injection.  Bier  made  similar  observations  and  while  at  times  certain 
clinical  improvement  followed  these  earlier  attempts  the  methods 
never  came  into  prominence  because  of  obvious  limitations.  In  the 
modern  use  of  transfusion  we  are  dealing  only  with  the  effort  at  sub- 
stituting or  making  good  a  serious  loss  of  serum  or  corpuscles  and 
every  effort  is  made  to  avoid  a  reaction  on  the  part  of  the  recipient. 

Normal  Human  Serum. — Auto  serotherapy. — The  use  of  normal  hu- 
man serum,  drawn  from  another  individual  or  from  the  patient  (auto- 
serotherapy)  for  either  subcutaneous  or  intravenous  reinjection,  is  not 
a  new  procedure.  The  use  of  normal  serum  in  hemorrhagic  diathesis 
in  particular  has  been  in  vogue  a  number  of  years.  (Weil,  1908.)  It 
is  probable  that  in  the  mechanism  of  clotting  a  colloidal  rearrange- 
ment of  sufficient  magnitude  is  brought  about  so  that  the  serum  be- 
comes toxic  for  the  homologous  organism,  and  that  it  is  this  change 
which  accounts  for  the  fact  that  the  serum  brings  about  a  general 
reaction. 

Serum  when  first  defibrinated  is  decidedly  toxic  to  the  homologous 
animal,  a  fact  that  should  be  kept  in  mind  in  judging  the  reaction  elicited. 
Freund  in  studying  this  question  noted  that  when  defibrinated  blood  was 
injected  in  experimental  animals  within  15  minutes  after  drawing  the 
same,  death  followed  very  promptly;  if  a  little  more  time  elapsed  the  ani- 
mal went  into  collapse;  if  injected  within  30  minutes  the  animal  reacted 
with  fever.  From  this  time  on  the  serum,  up  to  20  hours  after  preparation, 
produced  merely  a  very  slight  febrile  disturbance. 

In  recent  years  a  number  of  interesting  papers  have  been  published  deal- 
ing with  the  injection  of  homologous  serum,  especially  in  the  hemorrhagic 
diseases.  In  the  American  literature,  too,  the  method  is  very  favorably 
reported  (Freeman,  Huber,  MacFarlane,  Kaiser,  Sophian,  Hartmann, 
Belliboni,  Eosenberger,  LeClainche  and  Vallee,  Jousset,  Mosti,  Rosier, 
etc.) 

In  using  autoserotherapy  blood  is  drawn  from  a  vein  of  the  pa- 
tie^  and  this  is  permitted  to  clot— or  may  be  defibrinated.  The 


THE  NONSPECIFIC  AGENTS  17 

serum  drawn  from  the  clot  (or  after  centrifuging  the  defibrinated 
blood)  is  reinjected  intravenously,  usually  once  or  twice  during  the 
course  of  the  week.  Little  or  no  reaction  follows  the  procedure  and 
the  therapeutic  success  is  not  very  brilliant,  considering  the  amount 
of  time  consumed,  with  tho  manipulation.  Perry  substituted  horse 
serum  with  seemingly  good  results. 

Normal  Animal  Serum. — Horse  serum,  beef  serum,  goat  serum, 
sheep  serum,  chicken  serum,  to  mention  but  a  few  that  have  been 
used,  were  first  injected  subcutaneously,  in  more  recent  years  intra- 
venously; the  dosage  that  can  be  used  with  safety  varies  with  the 
serum,  its  age,  method  of  preparation,  whether  preservatives  have 
been  added  and  the  sensitization  of  the  patient.  As  much  as  250  c.c.  of 
beef  serum  have  been  given  intravenously  (in  anthrax)  without  injury; 
indeed  the  larger  doses  have  in  most  cases  been  more  satisfactory 
than  the  smaller  ones.  The  reaction  to  these  serums  is  as  a  rule  very 
mild,  only  occasionally  is  a  fever  and  chill  observed.  Before  in- 
jecting serums  of  this  type  a  skin  test  should  be  made  to  determine 
whether  the  patient  is  possibly  sensitive  to  the  serum  the  use  of 
which  is  contemplated.  With  repeated  doses  the  reaction,  contrary  to 
the  result  with  many  of  the  other  nonspecific  agents,  may  become 
more  severe,  even  when  the  injections  are  made  within  the  time  period 
usually  alloted  before  active  sensitization  will  occur.  Intravenous  in- 
jections must  always  be  made  very  slowly  even  when  there  is  no 
evidence  of  sensitization.  If  the  patient  has  become  sensitive  great 
caution  must  be  observed,  although  Smith  has  made  use  of  the  fact 
that  patients  become  sensitized  to  serum  injections,  for  therapeutic 
results.  He  found  that  when  patients  became  sensitive  to  serum  in- 
jection and  reacted  with  some  temperature  increase  and  a  general  sys- 
temic reaction,  a  definite  curative  effect  was  to  be  observed  on  local 
inflammatory  conditions  (gonorrheal  complications).  Normal  serum 
was  recommended  for  injection  in  cases  of  diphtheria  by  Bertin  as 
early  as  1895. 

Immune  Serum. — The  use  of  the  serum  of  convalescent  patients 
for  injection  either  subcutaneously  or  intravenously  is  a  procedure 
that  also  dates  back  for  a  considerable  time.  It  was  used  in  typhoid 
fever  with  some  success  but  the  most  extensive  application  has  possi- 
bly been  in  the  treatment  of  scarlet  fever,  and  more  recently  in  the 
treatment  of  influenza.  To  be  used  successfully  large  doses  must  be 
employed  and  the  treatment  given  early,  two  facts  that  suggest  very 
strongly  that  the  effect  is  due  less  to  any  antitoxic  or  antibacterial 
property  of  the  serum,  than  to  the  nonspecific  stimulating  effect  of 
the  serum  proteins. 

Weisbecker  had  used  subcutaneous  injections  of  convalescent  serum 
in  scarlet  fever  in  1897,  but  the  method  was  not  extensively  used  until 
Reiss  and  Jungmann  emphasized  the  value  of  the  treatment  with 
larger  doses.  From  80  to  100  c.c.  of  serum  are  now  commonly  em- 


18  PROTEIN  THERAPY 

ployed,  being  injected  intravenously  whenever  practical.  Render  bases 
his  dosage  on  the  body  weight,  injecting  2  c.c.  of  serum  per  kilo. 
Very  little  attention  has  therefore  been  paid  to  the  determination  of 
the  isoagglutinins  that  may  be  present  in  the  serum  injected  intrave- 
nously and  at  times  rather  severe  reactions  have  been  reported  (Gries- 
bach),  probably  because  of  the  neglect  of  this  precaution.  Of  course 
the  serum  used  should  be  tested  by  means  of  the  Wassermann  reaction 
before  injection. 

Antibacterial  Serums  and  Antitoxins. — Antitoxins  of  various  kinds 
and  Antibacterial  Serums  have  been  widely  used,  these  including  diph- 
theria and  tetanus  antitoxin,  antistreptococcus,  antipneumococcus,  anti- 
dysentery  serum,  etc.  This  paraspecific  serum  therapy,  as  it  is  com- 
monly termed,  has  found  extended  use  both  in  France  and  England,  and 
to  some  extent  in  this  country.  Such  serums  are  not  only  used  for 
injection — (intravenous,  intramuscular  and  subcutaneous) — but  have 
been  given  orally.  Paton  in  his  "New  Serum  Therapy"  discusses  this 
method  and  the  results  obtained  therewith. 

"In  1895  Bokenham  had  observed  that  the  administration  of  diphtheria 
antitoxin  seemed  effective  against  streptococcus  infection;  DQ  Minicis  the 
following  year  administered  diphtheria  antitoxin  orally  in  five  patients 
with  good  results;  in  1897  Lilienthal  observed  the  efficacy  of  Streptococcus 
Serum  in  a  variety  of  surgical  conditions,  while  McCallum  tried  injec- 
tions of  diphtheria  antitoxin  in  tuberculosis,  lupus  and  adnexal  inflam- 
mations with  good  results. 

"On  this  basis  Paton  began  his  work,  using  antitoxins  as  well  as  sheep, 
horse,  and  beef  serum  interchangeably  in  a  large  series  of  cases  and  vari- 
ous diseases,  with  at  times  very  interesting  results. 

Warier  took  up  this  study  in  France  and  quotes  a  considerable  litera- 
ture dealing  with  therapy  of  this  kind. 

"In  pneumonia  Talamon  in  1901  treated  about  115  cases  with  consid- 
erable success  with  diphtheria  antitoxin;  Mongour  used  it  in  broncho- 
pneumonia  and  pulmonary  abscesses  and  Launois  also  treated  several 
cases.  Deronet  and  Jeulin  applied  the  treatment  in  31  cases  of  pleurisy; 
their  favorable  report  was  confirmed  by  Faure  in  a  small  series  of  cases. 
Burkard  used  serum  in  the  treatment  of  exophthalmic  goiter  and  Bloch 
obtained  good  results  using  tetanus  antitoxin.  Weil  reported  on  the  use 
of  such  sera  in  hemophilia  as  well  as  in  peritonitis,  sepsis,  puerperal  in- 
fection, etc.  Freund  in  1911  tried  normal  horse  serum  in  the  toxemia 
of  pregnancy.  In  typhoid  Mongour  and  Cazamin,  Marotte  and  Oui  used 
diphtheria  antitoxin;  Albert  Levy  used  it  in  dysentery.  In  arthritis  L. 
Ramond  and  Chiray,  Passavy  and  Chauvet  and  Guithard  reported  excel- 
lent results.  Iritis  was  treated  by  the  same  means  and  in  erysipelas  Lau- 
nois, Apostolleaum,  Polak  and  Mayweg  reported  good  results." 

Cumston  has  but  recently  called  attention  to  the  fact  that  in 
France  paraspecific  therapy  has  been  commonly  employed  both  in  the 
army  and  in  civilian  practice,  particularly  in  ocular  infections.  Diph- 
theria antitoxin  is  usually  used  for  oral  administration  in  military 


THE  NONSPECIFIC  AGENTS  19 

practice  but  where  the  conditions  are  favorable  the  subcutaneous  and 
intravenous  use  is  preferred.  It  is  said  to  relieve  pain  and  induce  a 
pronounced  euphoria. 

The  dosage,  as  may  be  expected,  is  not  a  fixed  one.  The  serums  are 
in  this  case  given  not  for  their  antitoxic  property  but  for  their  nonspe- 
cific stimulating  effect.  A  very  small  dose  in  a  sensitive  patient  may  be 
sufficient  to  induce  a  severe  reaction ;  usually  however  the  dose  may  be 
fairly  large  after  a  careful  determination  has  been  made  as  to  the  de- 
gree of  sensitization  of  the  patient.  The  agents  of  this  type  have  the 
advantage  that  they  can  be  obtained  in  sterile  containers  ready  for 
administration.  They  do  not  as  a  rule  give  any  striking  therapeutic 
results  such  as  one  may  observe  from  the  more  toxic  agents  but  offer 
a  relatively  safe  means  of  experimentation  until  the  physician  be- 
comes more  or  less  familiar  with  therapy  of  this  type. 

Deutschmann  Serum. — The  general  increase  in  resistance  to  in- 
fection that  is  observed  after  the  use  of  yeast  led  Deutschmann  in 
1907  to  try  out  a  novel  method  of  this  principle.  He  immunized  horses 
with  yeasts  for  a  considerable  period  of  time  and  then  used  the  serum 
in  a  number  of  diseases.  He  was  interested  chiefly  in  eye  diseases, 
but  the  serum  was  tried  out  in  a  variety  of  acute  infections  as  well. 
He  had  observed  that  his  yeast-immunized  animals  all  became  more 
resistant  to  general  infection,  and  believed  that  this  change  in  re- 
sistance was  due  to  a  serum  alteration. 

The  serum  was  injected  into  patients  both  subcutaneously  and  in- 
travenously, but  in  relatively  small  dosage, — from  2  to  4  c.c.  In  his 
series  of  cases  there  were  24  pneumonias  treated  with  the  serum,  of 
whom  three  died.  In  four  of  the  cases  a  crisis  was  observed  immedi- 
ately after  the  injection.  In  all  of  the  cases  the  euphoria  following 
the  injection  was  well  marked.  The  serum  has  been  used  in  general 
sepsis,  erysipelas,  various  inflammatory  conditions, — furunculosis, 
otitis  media,  impetigo,  eczema, — and  with  seemingly  good  results  in  eye 
conditions — traumatic  inflammation — hypopyon  keratitis,  iridocy- 
clitis,  iritis,  etc.  (Bockhoff.) 

In  lupus  vulgaris  a  marked  local  inflammatory  reaction  was 
observed  as  with  all  other  similar  nonspecific  agents. 

Tuberculosis  Serum. — The  commonly  used  preparations  of  Mara- 
gliano  and  of  Marmorek  cause  reactions  in  tuberculous  patients  that 
have  been  ascribed  to  various  immunological  alterations  but  are  very 
probably  due  to  their  action  as  nonspecific  proteins.  The  temperature 
is  increased  after  injection,  focal  reactions  take  place,  there  is  an 
increase  in  the  amount  of  sputum,  etc.  Just  as  with  other  nonspe- 
cific agents  used  in  the  treatment  of  tuberculosis,  incipient  cases  are 
frequently  benefited,  advanced  cases  on  the  other  hand  are  unfavorably 
influenced. 

Related  Agents. — Plasma  Serum  has  been  used  particularly  by 
French  observers.  Grigant  and  Montier  have  used  the  method  in  the 


20  PROTEIN  THERAPY 

treatment  of  influenza.  Rabbit  plasma  is  mixed  with  human  serum 
and  injections  of  this  mixture  are  given  intravenously. 

Blister  Serum,  an  infrequently  used  method,  consists  in  producing  a 
local  vesicle  in  some  area  of  the  skin,  withdrawing  the  fluid  transudate 
and  reinjecting  the  same.  It  possesses  no  properties  of  unusual  ac- 
tivity. 

Pleural  Transudates  and  Exudates  (also  termed  autoserotherapy). 

Gilbert  at  the  Medical  Congress  at  Rome  in  1894  reported  that 
he  had  successfully  treated  pleuritic  effusions  by  withdrawing  a  limited 
amount  of  fluid  from  the  chest  and  reinjecting  the  same  under  the 
skin  of  the  patient.  The  resorption  of  the  pleural  exudate  was  said 
to  be  greatly  hastened.  A  long  list  of  clinicians  soon  published  re- 
ports with  the  method,  most  of  them  with  favorable  results — Fedde, 
Gerouzi,  Tchigaoff,  Nassetti,  Marcon,  Durand,  Schniitgen,  Duncan, 
Modinos,  Indelli,  Fiori,  Landmann,  Linser,  Spiethoff,  St.  Mello — a 
summary  of  the  work  having  been  collected  in  a  review  by  Fish- 
berg. 

The  technique  is  very  simple;  5  to  10  c.c.  of  fluid  are  withdrawn 
from  the  chest  on  alternate  days  or  at  longer  intervals  and  reinjected 
subcutaneously  without  withdrawing  the  needle  to  the  surface  of  the 
skin.  In  some  instances  a  very  slight  temperature  rise  has  been  noted 
to  follow  the  injections;  in  most  cases,  however,  no  reaction  follows. 
Zimmermann  studied  the  mechanism  involved  and  observed  that  a 
leukocytosis  followed  the  injection.  He  was  of  the  opinion  that  the 
reaction  was  due  to  autolytic  products  of  tissue  degeneration  that  were 
contained  in  the  pleural  fluid  and  made  the  observation  that  when  he 
injected  such  products  of  tissue  destruction — peptones — in  animals,  a 
leukocytosis  resulted.  Eisner  also  observed  this  leukocytosis. 

Lyter  has  recently  gone  over  the  subject  and  has  come  to  the  conclusion 
that  the  injections  of  pleural  fluid  have  little  or  no  influence  in  hastening 
the  absorption  of  the  exudate.  In  23  cases  carefully  followed,  treated  by 
withdrawing  5  c.c.  of  fluid  daily  and  reinjecting  the  same,  8  were  com- 
pletely reabsorbed  in  two  weeks'  time — 34%,  while  in  the  balance  the 
effusion  did  not  lessen  as  a  result  of  the  treatment.  Lyter  observed  prac- 
tically no  leukocytosis  and  in  only  two  of  the  8  rapidly  resorbing  cases 
did  he  observe  any  temperature  reaction  at  alL 

It  seems  probable  that  the  method  is  at  best  a  very  mild  stimulant 
of  resorption  because  the  nonspecific  response  is  practically  negligible 
as  far  as  the  effect  on  temperature  and  leukocytosis  is  concerned. 
Perkins  has  recently  modified  the  procedure  somewhat  in  that  he 
draws  a  larger  amount  of  fluid  from  several  patients,  pools  the  samples 
and  adds  the  same  to  citrated  saline  solution.  To  this  a  5%  solution 
of  carbolic  acid  is  added  (to  10%  of  the  total  volume).  Of  this  mix- 
ture he  begins  injections  of  from  1  to  2  c.c.  subcutaneously,  gradually 
increasing  the  dose  until  he  gives  from  10  to  25  c.c. 


THE  NONSPECIFIC  AGENTS  21 

Cerebrospinal  Fluid.— v.  Zielinski  has  published  results  obtained 
in  the  treatment  of  typhus  fever  with  subcutaneous  and  intravenous 
injections  of  cerebrospinal  fluid  drawn  from  the  patient.  The  dose 
was  usually  15  c.c.  and  he  claims  to  have  obtained  good  results  from 
such  injections. 

Joint  Fluid. — Dufour  and  Debray  announce  that  the  fluid  from  a 
gonococcus  process  in  a  joint  answers  all  the  requirements  for  an 
efficient  and  harmless  autogenous  vaccine  when  injected  subcutane- 
ously.  There  is  no  need  to  heat  or  sterilize  the  fluid;  they  injected 
it  under  the  skin  of  the  thigh,  and  state  that  the  general  symptoms, 
and  the  general  and  localized  pain  rapidly  subsided,  and  the  tem- 
perature gradually  declined  in  their  three  cases.  The  effect  on  the 
urethral  and  vaginal  processes  could  not  be  determined  as  local  meas- 
ures had  been  tried  there  as  usual. 

The  Local  Effects  of  Serum,  of  Normal  Salt  Solution  and  of  lodid 
Injections. — The  treatment  of  wounds  and  of  local  tissue  inflamma- 
tion by  means  of  local  injections  of  serum,  homologous  as  well  as 
foreign,  is  a  more  recent  development.  Miiller  has  discussed  the  effect 
and  the  possibilities  and  Wright  in  his  studies  on  local  tissue  resistance 
to  infection  has  also  made  use  of  this  method.  When  so  employed 
in  cellular  inflammation  the  injection  is  followed  by  marked  ameliora- 
tion of  the  local  symptoms,  pain,  tension  and  swelling  being  markedly 
diminished.  The  local  injection  of  physiological  salt  solution  is  said 
to  be  followed  by  a  similar  analgesia.  The  method  has  been  most 
extensively  employed  in  the  treatment  of  gonorrheal  complications, 
especially  epididymitis. 

As  a  rule  10  c.c.  of  serum  or  salt  solution  are  injected  into  the 
scrotum  near  the  site  of  the  inflammation. 

These  methods  are  related  to  Bier's  method  of  treatment  by 
passive  hyperemia.  As  a  matter  of  fact  Bier  has  called  attention 
to  the  effect  of  foreign  protein  injections  in  infectious  diseases  in 
a  very  early  paper  and  has  always  been  an  advocate  of  related 
measures. 


NATIVE  PROTEINS 

Von  den  Velden  seems  to  have  been  one  of  the  first  to  have  used 
native  protein  injections  in  therapy  with  the  distinct  thought  under- 
lying this  procedure  that  he  was  thereby  stimulating  certain  nonspe- 
cific fermentative  reactions  in  the  body  which  would  be  useful  in  in- 
creasing the  general  resistance  to  disease.  He  found  for  instance  that 
the  vasomotor  activity  around  the  local  pathological  area  was  in- 
creased, that  there  was  evidently  an  increase  in  the  lymph  flow,  of 
the  leukocytic  reaction,  etc. 

Ovalbumin  and  Seralbumin. — Von  der  Velden  at  first  used  solu- 
tions of  ovalbumin  and  seralbumin  in  5%  and  10%  solution.  This  he 


22  PROTEIN  THERAPY 

injected  subcutaneously  in  doses  of  from  5  to  10  c.c. ;  later  he  used 
intramuscular  and  intravenous  injections. 

Holler  has  also  used  ovalbumin.  The  general  reaction  is  negligible 
and  the  therapeutic  effect  not  striking. 

Milk. — The  intramuscular  injection  of  milk  was  introduced  by 
Schmidt  and  by  Saxl  in  1916  to  induce  a  protein  reaction,  i.  e.,  the 
typical  rise  in  temperature  observed  following  other  agents.  Milk 
offered  the  advantage  that  it  would  be  easily  available  to  the  profession. 
The  method  is  very  simple.  Ordinary  pasteurized  (or  fresh)  milk  is 
boiled  for  from  5  to  10  minutes  and  when  cooled,  from  5  to  10  c.c.  are 
injected  intragluteally,  or  into  other  muscles — arm,  back,  etc. 

The  injection  is  followed  in  some  instances  by  a  chill  (not  as  se- 
vere as  that  following  typhoid  vaccine),  and  by  a  temperature  rise 
that  reaches  its  maximum  in  from  6  to  8  hours  and  then  subsides  within 
24  hours.  A  well  marked  leukocytosis,  ranging  from  15,000  to  40,000, 
also  results.  Milk  has  a  decided  styptic  effect  when  so  injected  and 
as  Doellken  has  shown  is  of  particular  value  in  diseases  associated 
with  hemorrhages.  This  effect  is  probably  due  to  its  effect  on  the 
liver  parenchyma,  which,  together  with  the  bone  marrow,  seems  to 
be  especially  stimulated  by  the  milk  injections.  Thrombokinase  and 
fibrinogen  appear  in  increased  amounts  in  the  serum  after  injec- 
tion. Locally  there  may  be  considerable  pain  at  the  site  of  the  in- 
jection. 

Milk  being  composed  of  many  and  varying  elements,  efforts  have 
been  made  to  identify  those  components  that  might  be  most  effica- 
cious. The  bacterial  content  in  particular  has  been  held  responsi- 
ble for  the  reaction  produced  by  the  milk  injection.  Indeed  Bessau, 
Decastello  and  E.  F.  Mueller  believe  that  the  reaction  is  due  wholly 
to  the  bacteria  that  are  contained  in  the  milk,  and  Uddgren  found 
that  the  reaction  following  sterile  milk  injections  was  relatively  mild 
in  character.  She  has  determined  that  commercial  milk,  even  after 
boiling  for  from  three  to  five  minutes,  may  still  contain  a  few  viable 
organisms.  Boiled  for  ten  minutes  the  milk  was  always  found  to 
be  sterile.  Uddgren  believes  the  reaction  of  the  milk  is  due  to  bacterial 
derivatives  or  protein  split  products  contained  in  the  milk. 

Ryhmer,  who  obtained  rather  unsatisfactory  results  with  milk 
injections — he  tried  it  in  diphtheria  carriers,  in  hemorrhage,  in 
anemia,  osteomyelitis,  sepsis  and  Barlow's  disease — also  believes 
that  the  reaction  is  due  wholly  to  the  bacteria  contained  in  the 
milk  because  with  fresh  sterile  milk  he  obtained  practically  no  re- 
action. 

When  repeated  injections  of  milk  are  given  the  reaction  of  the  pa- 
tient may  increase  to  some  extent,  differing  in  this  manner  from  the 
effect  of  reinjection  when  bacteria  and  proteoses  are  used.  There  seems 
to  be  relatively  little  danger  of  sensitization  or  of  anaphylactic  shock 
following  repeated  milk  injections;  many  thousand  injections  have 


THE  NONSPECIFIC  AGENTS  23 

been  reported  and  but  few  cases  of  shock  following  the  repeated  in-  j 
jections  (Sachs,  Oppenheim,  Lubliner,  van  Randenborgh).    The  last  \ 
observer  is  of  the  opinion  that  some  of  the  milk  preparations  (caseosan, 
etc.)  are  more  apt  to  be  followed  by  shock  symptoms  than  are  milk 
injections. 

Where  shock  symptoms  have  occurred  it  is  by  no  means  ex- 
cluded that  part  of  the  injection  may  not  have  accidentally  reached  a 
vein.  Great  care  should  always  be  exercised  that  the  injections  are 
intramuscular. 

The  fact  that  there  is  relatively  very  little  sensitization  of  the 
patient  following  milk  injections  has  been  variously  accounted  for. 
The  human  organism  is  not,  as  a  matter  of  fact,  very  susceptible 
to  anaphylactic  shock  under  any  circumstances,  and  Salus  has  sug- 
gested that  in  the  case  of  the  milk  injections  the  fact  that  the  milk 
has  been  boiled  would  tend  to  dedifferentiate  it  and  diminish  the  ten- 
dency to  sensitization. 

Slawik  recommends  the  use  of  human  milk  in  place  of  cow's  milk, 
especially  in  the  treatment  of  infants.  He  found  that  both  wet-nurses 
and  atreptic  infants  were  refractory  to  such  injections,  there  being 
absolutely  no  temperature  response.  According  to  Epstein  adults  re- 
act to  human  milk  with  an  increase  in  temperature,  etc.,  just  as  they 
do  to  cow's  milk. 

Local  injections  of  milk  have  been  used  by  Weiss  and  others  in  the 
treatment  of  buboes  and  local  inflammatory  processes.  While  a 
general  reaction  results,  there  is  a  decided  local  effect  similar  to  that 
noted  when  serum  and  physiological  salt  solution  are  injected  locally. 
(Vide.) 

For  intravenous  injection  fat- free  milk  has  been  prepared  by 
thoroughly  extracting  the  milk  with  fat  solvents  and  later  carefully 
evaporating  the  solvent  that  may,  after  gross  separation,  still  be  present 
in  the  milk. 

Casein  (Aolan,  Caseosan). — Lindig  and  Miiller  both  proceeded  to  | 
refine  this  so-called  "milk  therapy"  by  using  purified  casein  in  its 
place.    This  has  the  advantage  of  being  a  chemically  constant  product, 
free   from  bacteria,   for  which   one  might  presumably   determine  a 
standard  dosage. 

Lindig  has  used  a  5%  solution.  This  is  prepared  by  adding  5 
grams  of  purified  casein  to  a  N-10  solution  of  sodium  bicarbonate 
(20  c.c.),  shaking  and  agitating  the  same  until  the  casein  is  all  dis- 
solved and  then  adding  80  c.c.  of  distilled  water.  Of  this  solution  from 
%  to  1  c.c.  is  given  intravenously.  Injections  are  followed  as  a  rule 
by  a  chill  in  about  1  hour,  some  headache  and  a  moderate  increase  in 
temperature — about  3°  F. 

Miiller  has  used  a  similar  casein  preparation  which  has  recently 
been  placed  on  the  European  market  under  the  trade  name  of  Aolan. 
While  Lindig  considers  that  the  casein  represents  the  active  substance 


24  PROTEIN  THERAPY 

that  is  responsible  for  the  reaction  that  follows  milk  injections, 
Muller  is  of  the  opinion  that  the  casein,  just  as  the  milk  itself,  rep- 
resents merely  a  foreign  body  and  that  the  other  constituents  of  the 
milk  will  also  give  a  similar  reaction. 

A  similar  preparation — Caseosan — has  also  been  recently  placed  on 
the  market.  Both  are  merely  solutions  of  casein  in  sterile  containers. 

Casein  occupies  a  rather  unusual  position  among  the  native  pro- 
teins because  of  the  rapidity  with  which  it  is  split  and  particularly 
because  it  is  hydrolyzed  .by  erepsin ;  the  latter  fact  would  make  the 
splitting  of  the  injected  casein  probable  in  almost  any  of  the  tissue 
fluids.  Riedel  calls  attention  to  the  fact  that  the  mono-  and  diamins 
derived  from  the  casein  would  act  as  powerful  activators  for  tissue 
activity  and,  as  a  result,  for  enzyme  activity. 

Gelatin. — The  use  of  gelatin  for  intravenous  injections  was  recom- 
mended a  number  of  years  ago  because  it  was  assumed  that  the 
gelatin  would  be  much  more  efficacious  in  retaining  water  in  the 
vascular  bed  in  cases  of  shock  and  after  severe  hemorrhage,  as 
the  gelatin  forms  a  hydrosol.  The  injections  were  at  times  followed 
by  evidences  of  a  nonspecific  reaction  of  mild  degree — chill,  sweating, 
and  febrile  rise.  Clark  has  recently  studied  the  reaction  of  rabbits  to 
such  injection.  The  possibility  that  tetanus  may  follow  injections 
of  gelatin,  especially  when  given  subcutaneously,  must  be  kept  in 
mind.  (Weber.) 

Plant  Proteins. —  Munch  has  reported  on  the  use  of  plant  "press- 
saft"  for  parenteral  injections.  In  this  country  a  number  of  such 
agents,  of  unknown  origin  or  composition,  supposedly  derived  from 
plants,  are  on  the  market  and  are  exploited  under  proprietary  names. 
A  rather  amusing  inconsistency  is  to  be  noted  in  that  these  non- 
specific proprietary  agents  are  prepared  for  specific  purposes,  that 
is  for  each  disease  there  is  recommended  a  specific  "nonspecific" 
agent. 

Nucleic  Acid  and  the  Nucleins. — Nucleic  acid  was  first  brought 
to  the  attention  of  the  scientific  world  at  a  meeting  of  the  Basel 
Natiirforscher  Gesellschaft  in  1874  when  Miescher  discussed  its  chem- 
istry. It  was  not,  however,  until  almost  twenty  years  later  that  Hor- 
baczewski  introduced  it  into  medical  practice  and  observed  its  leuko- 
cytic  stimulative  properties.  Maurek  shortly  after  reported  on  the 
effect  of  subcutaneous  injections  on  the  leukocytic  picture  and  on 
the  temperature  curve,  and  Netter  introduced  it  in  France.  It  was 
soon  extensively  used  in  a  number  of  infectious  diseases  and  in  a 
variety  of  degenerative  diseases  of  the  central  nervous  system,  such 
as  general  paralysis,  tabes,  etc.  Chantemesse  and  Parlavecchio  both 
studied  the  effect  of  nuclein  injections  on  antibody  formation,  finding 
that  both  alexins  and  agglutinins  were  increased,  while  Fox  and  Lynch 
have  in  very  recent  years  studied  the  effect  of  nuclein  injections  on 
the  leukocytosis  of  dogs.  Brown  and  Ross  have  studied  the  leukocytic 


THE  NONSPECIFIC  AGENTS  25 

reaction  in  connection  with  injections  in  a  series  of  mental  dis- 
eases. 

The  dosage  depends  on  the  preparation.  Usually  as  much  as  0.5 
gm.  of  the  sodium  nucleinate  is  given  subcutaneously,  this  being  fol- 
lowed by  a  leukocytosis  in  from  4  to  10  hours  after  the  injection  and 
a  febrile  reaction  which  may  persist  for  24  hours;  this  is  usually 
mild  in  character  and  does  not  as  a  rule  exceed  2°  F. 

A  modification  of  this  method  is  the  Nucleohexyl  recently  prepared. 
It  is  a  compound  of  nucleic  acid  and  hexamethylintetramin  that  is 
used  in  10%  solution  for  intravenous  injections.  The  dosage  is  about 
10  c.c.  Levy  claims  to  have  found  it  useful  in  the  treatment  of 
typhus  fever, 

PROTEIN  SPLIT  PRODUCTS 

That  protein  split  products  will,  on  injection,  increase  the  tolerance 
both  to  further  injections  and  resistance  against  infection  is  an  ob- 
servation that  has  been  made  quite  a  number  of  years  ago,  among 
others  by  Vaughan  and  his  associates  in  this  country.  It  is  only  in 
recent  years,  however,  that  the  various  split  products  of  proteins 
have  come  to  be  recognized  as  therapeutic  agents.  Nolf  has  used 
proteoses  in  diseases  associated  with  hemorrhage,  as  in  hemorrhagic 
diathesis,  paroxysmal  hemoglobinuria,  etc.,  with  the  idea  of  increas- 
ing the  coagulability  of  the  blood.  To  Liidke  belongs  the  credit  of 
first  using  proteoses  in  the  treatment  of  acute  infections.  Nolf  be- 
gan their  use  for  this  purpose  somewhat  later  and  since  then  a  large 
number  of  clinicians  have  published  their  results  with  this  dis^ 
tinctly  "protein  therapy"  as  it  came  to  be  termed. 

In  our  experience  a  variety  of  proteoses  (albumoses)  prepared  from 
different  proteins,  will  give  a  very  prompt  and  satisfactory  reaction. 
It  has  been  shown  at  various  times  that  the  primary  proteoses  are 
somewhat  more  toxic  than  the  secondary  proteoses  for  animals,  but  in 
therapeutic  injections  the  difference  in  effect  may  not  be  appreciable. 
Liidke  used  deuteroalbumoses,  these  being  now  prepared  commercially 
for  therapeutic  use  in  Germany. 

The  derivation  of  the  protein  split  product  that  is  used  is  of  con- 
siderable importance  in  regard  to  its  toxicity.  Schittenhelm  and 
Weichardt  in  their  studies  noted  the  difference  in  toxicity  of  protein 
split  products  derived  from  different  native  proteins.  Kaznelson  study- 
ing this  question  with  particular  reference  to  the  therapeutic  use  of 
deutero-albumoses  tried  out  deutero-albumose  prepared  from  fibrin, 
from  gelatin,  from  wheat,  horn,  silk,  etc.  Injected  subcutaneously 
they  were  all  followed  by  considerable  local  pain  at  the  site  of  the 
injection.  Intragluteally  the  local  reaction  of  these  albumoses  dif- 
fered little  from  that  following  milk  injection.  The  intravenous 
effect  differed  considerably.  Thus  the  hetero-albumoses  prepared  from 


26  PROTEIN  THERAPY 

fibrin  were  much  more  toxic  than  the  others.  Those  from  gelatin 
followed  next  in  the  severity  of  the  reaction  while  those  derived  from 
wheat,  horn,  silk,  etc.,  gave  little  or  no  reaction. 

From  the  studies  of  Baehr  and  Pick  it  seems  most  probable  that 
the  toxicity  of  protein  preparations  such  as  these  depends  to  a  large 
degree  on  the  presence  or  absence  of  the  cyclic  or  ring  compounds 
in  the  protein  molecule.  Perhaps,  too,  the  size  of  the  colloidal  aggre- 
gate is  of  importance  in  determining  the  reaction  after  intravenous  in- 
jection. 

The  dosage  of  the  Deutero-albumoses  and  of  the  other  primary 
and  secondary  proteoses  so  far  used,  has  varied.  In  our  own  work 
we  have  used  from  %  to  2  c.c.  of  a  2%  solution  of  secondary  proteose. 
Liidke  first  used  about  2  c.c.  of  a  2%  solution;  recently  he  has  in- 
jected from  1  to  2  c.c.  of  a  10%  solution;  Holler  used  1  c.c.  of  a  10% 
solution. 

Jobling  as  well  as  the  writer  have  been  under  the  impression  that 
small  doses  repeated  at  frequent  intervals  offer  the  best  mode  of 
administration.  Jobling  in  his  Harvey  Lecture  recommends  begin- 
ning with  a  dose  of  0.25  c.c.  of  a  1%  solution  and  determining  if  the 
patient  reacts  with  much  temperature.  If  there  is  no  general  reaction 
from  this  dose  a  somewhat  larger  dose  can  be  selected  for  injection 
the  following  day.  This  is  particularly  advisable  in  the  more  toxic 
forms  of  infectious  diseases;  in  arthritis,  on  the  other  hand,  it  may 
be  better  to  give  a  relatively  large  dose  (after  its  reactivity  is  known) 
at  the  beginning  and  induce  a  sharp  reaction.  The  reaction  follow- 
ing the  injection  depends  not  only  on  the  dose  but  on  the  type  of  dis- 
ease from  which  the  patient  is  suffering,  just  as  with  milk  injections. 
(Schmidt.) 

The  patient  does  not  become  sensitized  to  proteose  injections; 
rather  a  degree  of  tolerance  is  established,  so  that  following  or  re- 
peated injections  do  not  give  an  equal  response  on  the  part  of  the 
patient. 

In  animal  experimentation  there  is  some  evidence  that  sensitiza- 
tion,  at  least  to  the  higher  proteoses,  can  be  established.  In  the  hu- 
man there  has  been  no  evidence  of  this  effect,  at  least  as  far  as 
can  be  determined  from  the  clinical  reaction  that  follows  after  repeated 
injections. 

It  is  very  doubtful  to  my  mind  if  a  therapeutic  effect  can  be 
achieved  unless  a  general  reaction  is  brought  about  in  the  patient. 
Nolf  emphasizes  that  shock  should  be  avoided — "when  one  employs 
proteosotherapy  to  cure  a  patient  of  an  infectious  disease  one  should 
avoid  shock — at  least  the  violent  shock  which  I  have  described.  But 
it  seems  to  be  an  advantage  to  produce  a  mild  reaction  which  I  have 
called  the  'peptone  effect'  in  contrast  to  'peptone  shock.' " 

Efforts  of  many  workers  have  been  directed  in  producing  some 
agent  that  would  not  produce  a  severe  reaction — that  is,  the  nausea, 


THE  NONSPECIFIC  AGENTS  27 

chill,  sweating  and  fever — and  would  at  the  same  time  give  an  equally 
satisfactory  therapeutic  result. 

There  is  little  doubt  that  from  the  clinical  standpoints  such  an 
agent  would  be  a  very  desirable  one,  and  it  is  an  idea  that  should 
be  kept  in  mind.  But  we  are  confronted  with  the  probability  that,  as 
will  be  pointed  out  in  the  chapter  on  The  Focal  Reaction,  the  posi- 
tive phase  or  mechanism  of  recovery  after  nonspecific  injections  is 
a  function,  or  at  least  very  closely  related  to  the  degree  of  the 
negative  phase  or  the  intensification  of  the  disease  process  that  is 
clinically  manifest  in  the  reaction  of  the  patient.  Just  as  in  local 
foci  of  disease  a  marked  augmentation  of  the  inflammation,  both 
after  specific  vaccine  injections  (as  after  the  injection  of  "Arthigon" 
Schultz  found  that  gonorrheal  lesions  healed  best  after  severe 
reactions)  or  nonspecific  injections  is  followed  as  a  rule  by  clinical 
improvement,  so  in  the  general  infections  a  relatively  severe  re- 
action is  more  frequently  followed  by  an  abortive  recovery 
than  when  the  reaction  is  very  mild  or  absent.  I  cannot  too  strongly 
emphasize,  however,  that  the  utmost  care  and  judgment  must  be  ex- 
ercised and  a  considerable  degree  of  experience  must  be  gained  in 
the  treatment  of  such  diseases  as  arthritis  or  of  local  inflammations 
before  the  attempt  is  made  to  treat  general  infections,  unless  the 
physician  wishes  to  court  disaster. 

The  entire  question  of  dosage  and  of  the  proper  reaction  is  still 
an  open  one.  I  believe  that  the  method  of  Holler  is  a  safe  one  and 
one  that  can  be  recommended.  Holler  injected  his  cases  of  in- 
fectious diseases  with  a  daily  dose  of  deutero-albumose  that  was  just 
sufficient  to  elicit  a  mild  reaction.  In  some  diseases  he  administered 
two  doses  daily.  This  method  is  certainly  much  safer  than  the  ad- 
ministration of  a  single  huge  dose  which  may  be  more  than  the  patient 
can  bear. 

v.  Biedl  has  made  use  of  Histamin,  using  0.5  mg.  for  intravenous 
injections.  The  results  were  not  particularly  satisfactory,  nor  were 
they  much  better  when  Witte  Peptone  was  employed. 

On  the  other  hand  both  Nolf  and  Gow  have  used  Witte  Peptone 
with  evident  success.  Gow  employs  a  10%  solution.  This  is  made 
up  by  dissolving  10  gm.  of  the  dry  peptone  in  about  5  c.c.  of  hot 
freshly  distilled  water  and  bringing  the  volume  up  to  100  c.c.  Of 
this  from  8  to  10  c.c.  are  slowly  injected  intravenously. 

The  effect  of  the  intravenous  injection  of  various  split  products 
of  proteins  both  from  the  physiological  as  well  as  the  pharmacological 
standpoint  has  been  intensively  studied  both  in  this  country  and  in 
Europe  and  the  literature  is  so  well  known  and  readily  available  that 
it  will  not  be  necessary  to  enter  into  it  here.  The  effect  of  the  intra- 
venous injection  of  Histamin  has  been  more  recently  studied  by 
Dale  and  Laidlow. 


28  PROTEIN  THERAPY 

They  found  that  in  cats  the  injection  of  from  1  to  2  mg.  per  kilo,  was 
followed  by  a  marked  fall  in  blood  pressure,  there  was  a  clumping  of  the 
blood  platelets  (for  the  significance  of  the  clumping  of  blood  platelets  and 
its  bearing  on  anaphylaxis  the  article  of  v.  Behring  is  of  interest),  a  leuko- 
penia — the  leukocytes  stick  to  the  lining  of  the  vessels — and  in  a  relative 
polycythemia  with  increased  viscosity.  These  latter  changes  are  due  to  the 
increased  permeability  of  the  capillaries,  as  a  result  of  which  they  esti- 
mated that  about  40  per  cent,  of  the  plasma  was  lost  from  the  vascular  bed. 

ENZYMES 

Trypsin. —  A  method  that  was  considerably  exploited  some  years 
ago  was  the  so-called  Enzyme  Treatment  of  cancer,  advocated  by 
Beard,  which  consisted  in  the  subcutaneous  injection  of  a  trypsin 
solution.  It  is  very  problematical  whether  any  malignant  disease 
was  ever  actually  cured  by  the  injections;  focal  reactions  were  of 
course  noted,  with  a  diminution  of  the  size  of  the  larger  tumors  be- 
cause of  the  increase  in  the  autolytic  processes  in  the  neoplasm.  The 
injection  was  practically  always  followed  by  a  general  reaction  on 
the  part  of  the  patient,  evidenced  by  the  chill,  sweating  and  tempera- 
ture rise.  After  this  acute  reaction  the  patient  would  have  several 
days  of  relative  comfort.  Amylopsin  was  usually  combined  with  the 
trypsin  for  injection. 

Leukocytic  Extracts. — Leukocytes  contain  antibacterial  substances 
(Moxter,  Petterson,  Schneider)  and  an  effort  was  made  to  utilize 
this  property  therapeutic  ally.  Petterson  used  leukocytic  extracts  in 
dogs  that  were  at  the  same  time  injected  with  anthrax  bacilli;  there 
was  evidence  of  an  increased  resistance.  Later  he  used  a  similar 
method  in  testing  the  increased  resistance  of  guinea  pigs  treated  with 
leukocytic  extracts  and  infected  with  typhoid  bacilli.  Opie  made 
similar  experiments  with  dogs  and  later  Hiss,  and  Hiss  and  Zinsser 
carried  the  method  to  actual  trial  in  human  infectious  diseases. 
Leukocytes  were  as  a  rule  obtained  from  rabbits,  washed  and  sus- 
pended in  distilled  water.  Usually  the  entire  suspension  was  in- 
jected. Leukocytic  extracts  have  been  used  in  the  treatment  of 
pneumonia,  staphyococcus  infections,  erysipelas,  etc.,  with  apparently 
favorable  results. 

Considering  the  enzyme  content  of  the  polymorphonuclear  leu- 
kocyte it  seems  probable  that  the  injection  really  represents  a  mix- 
ture of  enzyme  and  heterologous  protein,  as  far  as  the  patient  is 
concerned;  the  injection  is  followed  by  a  leukocytosis  (Alexander), 
but  otherwise  with  little  general  constitutional  reaction.  Leukocytic 
extracts  have  been  placed  on  the  market  for  therapeutic  use,  and 
Archibald  and  Moore,  Leonard  and  Harmer  have  published  results 
obtained  after  the  injection  of  leukocytic  extracts.  Tunnicliff,  who 
has  recently  studied  the  effect  of  leukocyte  injections,  finds  that  the 
leukocytosis  that  is  observed  after  the  injection  persists  for  from 


THE  NONSPECIFIC  AGENTS  29 

1  to  4  days  and  that  the  leukocytes  are  particularly  active  (young 
forms). 

TISSUE  EXTRACTS 

Tumor  Autolysates. —  Efforts  to  influence  disease  processes  by 
means  of  autolysates  from  tissues  and  tissue  extracts  have  centered 
largely  about  malignant  neoplasms  and  a  considerable  number  of 
substances  have  been  used  by  clinical  observers.  The  work  of  Beard 
has  already  been  mentioned;  the  fact  that  tumor  cells  seem  very 
rich  in  heterolytic  proteoclastic  enzyme  (Wolff  and  Blumenthal) 
stimulated  repeated  efforts  to  prepare  some  substance  from  tumor 
juice  that  would  have  a  therapeutic  action.  All  substances  so  far 
used  cause  a  typical  protein  reaction  and  are  without  specific  action 
on  tumor  cells.  The  most  recent  report  of  such  a  preparation  is 
that  of  Joannovics  and  his  associate  Scherber.  Bier  and  Sticker  be- 
gan similar  studies  some  twenty  years  ago,  using  foreign  proteins 
(foreign  serum,  lymph,  organ  juices)  combined  with  atoxyl. 

Cartilage  Extracts. — Heilner  in  recent  years  prepared  an  extract 
from  cartilage  called  "sanarthrit"  which,  injected  in  chronic  arthritis, 
causes  in  some  cases  marked  alleviation  of  the  symptoms.  Heil- 
ner introduced  the  substance  for  the  treatment  of  gout,  on  the  as- 
sumption that  in  gouty  diathesis  the  cartilage,  because  of  its  chemical 
structure,  offered  a  site  of  particular  affinity  for  the  deposition  of 
uric  acid  and  related  compounds.  Therefore  the  injection  of  such 
material  in  a  soluble  form  might  aid  in  the  elimination  of  the  exciting 
metabolic  products.  It  was  soon  found,  however,  that  other  arthritic 
processes,  infectious  in  origin,  were  also  influenced  by  the  injections 
so  that  the  theory  was  no  longer  tenable.  It  is  now  the  expressed 
opinion  of  a  number  of  observers  that  the  reaction  is  merely  a  non- 
specific one  and  similar  in  character  and  in  its  therapeutic  possibilities 
and  limitations  to  the  other  agents  of  this  group. 

Vascular  Extracts. — The  most  recent  preparation  of  this  nature 
is  an  extract  of  vascular  tissue  (blood  vessel  walls,  etc.)  which  is 
said  to  have  some  effect  in  arteriosclerosis. 

Organotherapy.— Borchardt,  in  recent  communications,  has  made 
the  statement  that  all  the  tissue  extracts,  unless  they  offer  very  definite 
glandular  substitution,  as  thyroid  extracts  do,  or  contain  enzymes 
(and  are  therefore  enzymatic  agents)  represent  merely  nonspecific 
agents  which  stimulate  the  organism  in  a  nonspecific  way.  It  is  at 
least  very  probable  that  in  a  measure  their  effect  is  due  to  such 
activity. 

Borchardt  is  also  of  the  opinion  that  the  injection  of  relatively 
small  amounts  of  blood  subcutaneously  (Weinland)  and  the  injec- 
tion of  marrow  extracts  (Danilewski,  Fowler,  etc.)  as  well  as  splenic 
extracts  have  their  therapeutic  basis  on  the  same  nonspecific  stimula- 
tion of  the  hematopoietic  system. 


30  PROTEIN  THERAPY 

Esch  considers  the  results  obtained  with  organotherapy  in  men- 
strual disturbances  from  the  same  point  of  view.  As  proof  of  the 
plasmaactivation  Borchardt  brings  a  number  of  interesting  experi- 
ments. Using  immunized  rabbits  he  has  found  that  the  injection  of 
asthmolysin  (0.0008  adrenalin  and  0.04  infundibular  extract),  of 
spermin  and  also  of  thyroid  extract  greatly  increased  the  titer  of  the 
immune  bodies  in  the  serum.  The  thyroid  extract  was  active  even 
when  given  by  mouth.  As  a  result  of  his  experiments  he  considers 
any  of  these  agents  useful  in  the  infectious  diseases, 

THE  VACCINES 

Before  taking  up  the  question  of  the  use  of  vaccines  in  produc- 
ing a  nonspecific  response  it  may  be  well  to  quote  briefly  from  a  re- 
cent paper  of  Wright.  Inasmuch  as  Wright  has  done  more  than  any 
other  immunologist  to  emphasize  the  factor  of  strict  specificity  in 
vaccine  therapy,  introduced  the  method  of  estimating  such  specific  re- 
sponse on  the  part  of  the  patient  by  means  of  the  opsonic  index, 
recommended  the  use  of  autogenous  vaccines,  etc.,  it  is  but  fitting 
to  record  his  present  attitude. 

"Let  me  start  quite  at  the  beginning.  Long  after  the  principle  of  pro- 
phylactic inoculation  had  established  itself  in  medicine,  it  was  accepted 
that  to  inoculate  microbes  into  the  already  infected  system  would  be 
as  illogical  as  to  instill  further  poison  into  an  already  poisoned  system. 
Pasteur  was  the  first  to  teach,  us  here  a  distinction.  He  pointed  out,  in 
connection  with  immunization  against  rabies,  that  a  vaccine  might  legiti- 
mately come  into  application  in  the  incubation  period.  That  was  the  be- 
ginning of  therapeutic  immunization;  and  from  that  time  forth  it  was 
recognized  that  you  may  legitimately  inoculate  in  the  incubation  stage, 
and  try  to  get  in  advance  of  the  infection.  But  it  was  in  everybody's 
mind  that  immunization  took  10  days  to  establish  itself.  When  I  showed 
in  connection  with  antityphoid  inoculation  that  bactericidal  substances 
were  very  rapidly  elaborated,  it  became  plain  that  this  involved  shifting 
the  old  landmarks  and  taking  in  further  territory  for  therapeutic  immuni- 
zation, and  one  had  to  ask  oneself  all  sorts  of  penetrating  questions.  One 
had  to  ask  oneself  in  connection  with  'generalized  infections'  at  what  par- 
ticular stage  of  the  infection  one  was  to  regard  the  body  as  overmastered 
by  the  bacterial  poison,  and  incapable  of  further  immunizing  response. 
Again,  in  connection  with  'localized  infections'  one  had  to  inquire  whether 
they  should  not  be  envisaged  as  general  infections  indefinitely  arrested 
in  their  incubation  stage,  and  whether  they  might  not,  in  consonance 
with  that,  be  brought  within  the  sphere  of  inoculation. 

"Further  consideration  suggested  that  the  problem  of  therapeutic  in- 
oculation can  be  approached  also  from  a  point  of  view  different  from  that 
taken  up  by  Pasteur.  With  respect  to  immunizing  response,  the  body  had 
been  visualized  as  a  single  and  undivided  unit.  That  is  clearly  erroneous. 
One  region  of  the  body  may  be  making  immunizing  response  while  the 
other  is  inactive.  For  instance,  in  the  stage  of  incubation  it  is  presumably 


THE  NONSPECIFIC  AGENTS  31 

only  the  region  which  is  actually  harboring  the  microbe,  and  in  the  stage 
of  generalized  infection  it  is  presumably  the  entire  body  which  is  incited 
to  respond.  And  again,  in  localized  infection  we  may — making  here  some 
reserves — assume  that  we  have  only  localized  response. 

"Placing  ourselves  at  this  point  of  outlook,  therapeutic  immunization 
will,  it  is  clear,  be  theoretically  admissible  so  long  as  there  remains  in  the 
body  any  part  which  is  not  already  making  its  maximum  immunizing 
response.  And  the  program  of  therapeutic  inoculation  would  accord- 
ingly consist  in  exploiting  in  the  interest  of  the  infected  regions  of  the 
body  the  immunizing  responses  of  the  regions  which  are  uninfected. 

"Results  of  Vaccine  Therapy 

"Keeping  that  now  in  view,  let  me  try,  very  briefly,  to  tell  you  what  are, 
in  my  view,  the  results  which  have  been  achieved  by  applying  this  thera- 
peutic method.  I  can  do  that  in  a  very  few  words. 

"In  every  form  of  infection  a  certain  quota  of  unequivocal  successes 
may  be  credited  to  the  method,  and  especially  successful  results  have  been 
obtained  in  furunculosis  and  acute  inflammatory  sycosis;  in  'poisoned 
wounds' — meaning  by  that  localized  cellulitis  set  up  by  a  streptococcus  in- 
fection; in  streptococcal  infections  taking  the  form  of  lymphangitis,  in 
erysipelas;  in  tubercular  adenitis,  tubercular  joint  infections,  tubercular 
dactylitis,  tubercular  orchitis,  and  tuberculous  infections  of  the  eye,  es- 
pecially in  phlyctenules  of  the  conjunctiva;  again  in  bronchitis,  in  chole- 
cystitis, and  gonorrheal  rheumatism.  The  most  dramatic  and  convincing — 
convincing  because  here  no  other  therapeutic  measures  are  employed  as 
adjuncts — are  the  successes  obtained  in  streptococcal  lymphangitis,  in 
streptococcal  cellulitis — I  am  thinking  of  those  cases  which  have  already 
been  incised  without  striking  benefit — and  in  conjunctival  phlyctenules. 

"When  we  analyze  the  successes  and  failures*  of  vaccine  therapy  the 
following  points  come  out  quite  clearly: — 

"(1)  Vaccine  therapy  is  generally  unsuccessful  where  the  infection — 
as  in  phthisis — is  producing  constitutional  disturbance  and  recurring 
pyrexia. 

"(2)  Vaccine  therapy  is  also  generally  unsuccessful  where  we  have  to 
deal  with  unopened  abscesses,  or  sloughing  wounds  with  corrupt  discharges. 

"(3)  In  long-standing  infections  vaccine  therapy  is  much  less  success- 
ful than  in  recent  infections. 

"To  see  what  auxiliary  measures  should  be  applied  in  these  cases,  I 
must  take  you  back  for  a  moment  to  the  region  of  general  principles.  .  .  . 

*I  here,  as  clear  thinking  exacts,  exclude  from  the  failures  of  vaccine 
therapy  the  failures  of  that  preventive  inoculation  against  individual  infections 
to  which  vaccine  therapy  is  the  usual  precursor.  The  efficacy  of  such  prophy- 
lactic procedure  is  a  question  apart.  But  I  may  usefully  point  out  to  you 
that  the  superior  credit  which  attaches  to  antityphoid  inoculation,  and  preventive 
inoculation  against  infective  diseases  generally,  as  compared  with  preventive 
inoculation  against  what  I  may  call  individual  infections,  is  probably  attributable 
to  the  fact  that,  in  the  case  where  we  are  dealing  with  an  infective  disease,  the 
external  circumstances  are  as  favorable  to  success  as  they  are  in  the  case  of 
inoculation  against  "individual  infections"  unfavorable. 


32  PROTEIN  THERAPY 

"Nonspecific  Immunization 

"In  the  foreground  stands  the  question  of  nonspecific  immunization. 
That  immunization  is  always  strictly  specific  counts  as  an  article  of  faith; 
and  it  passes  as  axiomatic  that  microbic  infections  can  be  warded  off  only 
by  working  with  homologous  vaccines;  and  that  we  must  in  every  case 
before  employing  a  vaccine  therapeutically,  make  sure  that  the  patient  is 
harboring  the  corresponding  microbes.  I  confess  to  having  shared  the  con- 
viction that  immunization  is  always  strictly  specific.  Twenty  years  ago, 
when  it  was  alleged,  before  the  Indian  Plague  Commission,  that  anti- 
plague  inoculation  had  cured  eczema,  gonorrhea,  and  other  miscellaneous 
infections,  I  thought  the  matter  undeserving  of  examination.  I  took 
the  same  view  when  it  was  reported  in  connection  with  antityphoid  inocu- 
lation that  it  rendered  the  patients  much  less  susceptible  to  malaria.  Again, 
seven  years  ago,  when  applying  pneumococcus  inoculations  as  a  preventive 
against  pneumonia  in  the  Transvaal  mines,  I  nourished  exactly  the  same 
prejudices.  But  here  the  statistical  results  which  were  obtained  in  the 
Premier  Mine  demonstrated  that  the  pneumococcus  inoculations  had,  in 
addition  to  bringing  down  the  mortality  from  pneumonia  by  85  per  cent, 
reduced  also  the  mortality  from  'other  diseases'  by  50  per  cent.  From  that 
on  we  had  to  take  up  into  our  categories  the  fact  that  inoculation  produces 
in  addition  to  'direct'  also  'collateral'  immunization.  This  once  recognized, 
presumptive  evidence  of  collateral  immunization  began  gradually  to  filter 
into  our  minds.  Among,  I  suppose,  many  thousands  of  patients  treated 
by  vaccine  therapy  in  private  and  in  hospital,  it  happened  every  now  and 
then  that  a  patient  was  treated  with  a  vaccine  which  did  not  correspond 
with  his  infection,  and  that  that  patient  indubitably  benefited.  Again, 
it  was  not  an  uncommon  experience  for  the  subjects  of  a  very  chronic  in- 
fection (such  as  pyorrhea)  who  were  treated  first  by  a  stock  vaccine,  and 
afterwards  with  an  auto-vaccine,  to  assert  that  they  derived  more  benefit 
from,  and  to  ask  to  be  put  back  upon  treatment  by  the  stock  vaccine. 

"From  such  cases  hints  are  conveyed  to  us  that  there  may  exist  a  use- 
ful sphere  of  application  for  collateral  immunization;  and  that  such  sphere 
may,  perhaps,  be  found  in  those  cases  where  the  infection  is  of  very  long 
standing,  and  where  the  patient  has  become  very  sensitive  to,  and  has 
probably  come  very  near  the  end  of  his  tether  in  the  matter  of  immunizing 
response  to,  the  particular  species  or  strain  of  microbe  with  which  he  is 
infected.  It  will,  with  regard  to  such  patients,  be  remembered  that  they 
constitute  the  third  of  those  three  classes  of  cases  to  which  I  referred  to 
at  the  ouset  of  this  lecture  as  very  intractable  to  vaccine  therapy. 

"We  are,  however,  here  considering  primarily  the  question  of  principle; 
and  in  connection  with  this  what  is  of  fundamental  importance  is :  that 
we  should  discard  the  confident  dogmatic  belief  that  immunization  must 
be  strictly  specific,  and  that  we  should  in  every  case  of  failure  endeavor  to 
make  our  immunization  more  and  more  strictly  specific.  We  should  instead 
proceed  upon  the  principle  that  the  best  vaccine  to  employ  will  always  be 
the  vaccine  which  gives  on  trial  the  best  immunizing  response  against 
the  microbe  we  propose  to  combat. 

"I  would  point  out  that  this  would  almost  certainly  not  involve  any 
revolutionary  change  in  the  accepted  practice  in  either  serum  therapy  or 


THE  NONSPECIFIC  AGENTS  33 

in  prophylactic  or  ordinary  therapeutic  inoculation.  But  it  would  mean 
taking  into  account  in  cases  which  proved  intractable  to  treatment  with 
the  homologous  vaccine  the  possibility  of  seeking  for  collateral  immuniza- 
tion by  inoculating  a  microbe  or  mixture  of  microbes  other  than  that  with 
which  the  patient  is  infected.  The  trial  of  this  procedure  might  perhaps 
recommend  itself  where  from  the  outset  there  is  very  little  immunizing 
response  to  the  homologous  vaccine,  and  also  where,  as  in  long-standing 
cases  of  tubercule  or  streptococcus  infection,  the  power  of  direct  immuniz- 
ing response  to  the  corresponding  vaccines  is  becoming  exhausted." 

This  use  of  bacterial  vaccines  for  "collateral  immunization"  as 
Wright  uses  the  term,  or  for  nonspecific  stimulation,  is  a  modern  con- 
ception that  dates  practically  from  the  work  of  Renaud  and  of  Kraus. 
The  former  used  typhoid  vaccine  in  the  treatment  of  a  number  of  non- 
typhoidal  diseases ;  the  latter  treated  typhoid  patients  with  colon  vac- 
cine, and  then  proceeded  to  treat  puerperal  infection  and  other  acute 
infections  with  typhoid  and  colon  vaccines  with  remarkable  results. 
Until  this  time  the  fear  of  overdosage  had  kept  back  investigation  in 
this  particular  field.  The  disastrous  effects  that  had  at  times  followed 
the  injection  of  tuberculin  in  tuberculosis  had  made  a  profound  impres- 
sion on  medical  men,  and  the  emphasis  placed  on  the  negative  phase  of 
the  opsonic  curve  after  vaccine  injection  had  a  similar  effect.  With 
the  introduction  of  the  sensitized  vaccines  of  the  French  school  larger 
doses  came  to  be  used,  but  here  again  a  generalized  reaction  was 
avoided.  Occasionally  one  finds  records  of  more  heroic  dosage  and 
cures  following  on  general  reactions;  thus  Szily  cured  a  severe 
ophthalmoblennorrhea  with  several  large  doses  of  gonococcus  vaccine. 

Following  the  publication  of  Kraus's  results  a  large  number  of 
observers  have  used  heterovaccinotherapy  in  the  treatment  of  dis- 
eases of  various  kinds.  The  reaction  of  these  various  bacterial  vac- 
cines varies  of  course;  in  general,  however,  the  following  bacteria 
have  given  results. 

Typhoid  Vaccine. — The  toxicity  varies  greatly  with  the  age  and 
the  strain.  For  convenience  the  vaccine  is  usually  made  up  with  100 
million  organisms  to  the  cubic  centimeter,  of  this  approximately  25 
to  50  million  may  be  given  at  the  first  dose  if  the  particular  vaccine 
is  not  too  toxic;  great  care  must  be  observed.  Typhoid  vaccine  is 
followed  by  a  prompt  chill  and  temperature  reaction,  usually  by  a 
leukocytosis.  Headache  is  a  common  accompaniment. 

Colon  Vaccine. — Colon  vaccine  is  usually  followed  by  a  severe 
reaction,  which  may,  however,  be  delayed  for  several  hours  after  the 
injection.  Headache  is  usually  severe  after  several  hours.  It  has 
been  used  more  frequently  by  English  observers.  The  dosage  should 
not  exceed  25  million  for  the  first  intravenous  injection;  for  later  re- 
actions this  may  be  increased. 

Dysentery. — Dysentery  strains  of  all  types  when  injected,  both 


34  PROTEIN  THERAPY 

subcutaneously  or  intravenously,  are  relatively  toxic  and  resemble 
typhoid  and  colon  vaccines  in  their  general  effects. 

Cholera,  prodigiosus,  proteus,  and  a  number  of  other  organisms 
have  been  injected  intravenously  by  various  observers. 

Meningococci. — The  dose  used  is  usually  about  100  million.  The 
injection  is  followed  by  a  prompt  chill  that  has  its  onset  in  from  15 
minutes  to  one  hour  and  lasts  usually  a  half  hour.  Headache  is  com- 
mon, nausea  and  vomiting  quite  exceptional.  The  temperature  rise  is 
marked  and  reaches  its  maximum  in  from  6  to  8  hours.  Herpes  has 
been  commonly  observed  after  the  injections. 

Gonococci. —  Dosage  and  reaction  similar  to  the  meningococcus. 
Leukocytosis  is  well  marked  with  both  types  of  organisms  and  reaches 
a  maximum  in  from  5  to  7  hours.  With  the  gonococcus  vaccine  herpes 
is  less  frequent. 

Streptococci. —  The  streptococcus  is  evidently  not  as  toxic  as  the 
typhoid  and  colon  bacilli,  and  the  reaction  is  frequently  delayed  from 
8  to  10  hours.  A  dosage  of  100  million  is  usually  followed  by  only 
a  mild  temperature  reaction.  A  chill  is  not  so  common  and  the  leu- 
kocytosis  is  lacking.  The  vaccine  does  not  seem  to  be  a  good  agent 
for  nonspecific  stimulation. 

Staphylococci. — Similar  in  dosage  and  in  reactivity  to  the  strep- 
tococcus vaccine.  Followed  by  a  leukocytosis  of  considerable  extent 
and  has  been  found  more  useful  than  the  streptococcus  vaccine. 

Pyocyaneus. — Pyocyaneus  Vaccine  was  one  of  the  first  used  for 
heterovaccinotherapy  (by  Rumpf  in  the  treatment  of  typhoid  in 
1893).  Its  use  has  not  been  extensive  enough  to  justify  any  con- 
clusions as  to  its  value.  Dollken  has  used  it  in  the  treatment  of 
gummata. 

Pneumococcus. — In  dosage  and  reaction  similar  to  the  strepto- 
coccus, with  a  certain  degree  of  latitude  with  different  strains.  The 
leukocytic  response  is  not  marked ;  indeed  may  at  times  be  absent. 

Influenza  Bacilli. — Influenza  bacilli  injected  intravenously  have 
been  given  in  doses  of  from  50  to  100  million  organisms  with  relatively 
little  reaction  on  the  part  of  the  patient.  There  is  as  a  rule  no  chill, 
but  the  temperature  response  may  be  from  2°  to  3°  F.  several  hours 
after  the  injection. 

Diphtheroids. —  Both  diphtheroids  and  diphtheria  bacilli  seem  to 
produce  little  reaction  when  injected  intravenously.  A  dosage  of 
from  25  to  200  has  been  injected  intravenously,  followed  after  a  long 
latent  period  (10  hours)  by  some  general  reaction,  slight  chill,  tem- 
perature rise  of  from  1°  to  2°  F.  and  headache.  Usually  there  is  no 
leukocytosis. 

While  all  these  organisms  may  produce  some  reaction,  either 
mild  or  severe,  they  are  by  no  means  quite  comparable  in  their  effect 
on  the  leukocytic  response.  Schittenhelm,  Weichardt  and  Greissham- 
mer  have  called  attention  to  some  of  the  differences  that  exist  follow- 


THE  NONSPECIFIC  AGENTS  35 

ing  the  intravenous  injection  of  different  kinds  of  bacteria,  certain 
organisms  being  followed  by  a  prolonged  leukopenia  instead  of  a 
leukocytosis,  others  producing  myelitic  stimulation,  others  a  lym- 
phatic stimulation,  etc.  Dollken  in  his  recent  discussion  and  study  of 
heterobacteriotherapy  brings  out  the  fact  that  the  stimulation  by 
different  bacteria  may  not  be  omnicellular,  but  rather  selective;  that 
the  clinical  result,  too,  is  by  no  means  independent  of  the  kind  of 
organism  injected.  Thus  he  found  that  while  pyocyaneus  vaccine 
was  effective  in  gummata,  a  pseudodiphtheria  vaccine  was  quite 
without  effect.  In  neuralgia  a  prodigiosus  vaccine  gave  an  excellent 
clinical  result,  while  cholera  and  dysentary  vaccine  was  not  followed 
by  equal  clinical  improvement.  In  a  like  measure  in  the  treatment 
of  acne  neither  prodigiosus  nor  pyocyaneus  vaccine  proved  useful, 
while  the  autogenous  vaccine  was  promptly  followed  by  improve- 
ment. 

The  injection  of  vaccines  is  not,  like  milk,  followed  by  any 
styptic  effect;  on  the  other  hand,  they  are  not  as  a  rule  hemolytic, 
as  nucleohistone  and  albumoses  may  be.  The  resistance  to  rein- 
jection  also  differs  with  the  different  organisms.  Thus  there  is  a 
rapid  tolerance,  or  increased  resistance  established  to  typhoid, 
pyocyaneus,  pseudodiphtheria  and  several  other  vaccines,  while  milk, 
representing  a  native  protein,  may  at  times  become  more  marked  in 
its  effect  with  subsequent  injections. 

Mixtures  of  vaccines  have  also  been  employed.  Thus  the  "Arthi- 
gon"  of  Bruck  contained  a  number  of  strains  of  gonococci  and  10% 
of  protargol  and  was  used  extensively  in  Germany  in  the  treatment 
of  gonorrheal  complicationi.  "V accinurin"  is  a  recent  mixture  rec- 
ommended by  Dollken  for  use  in  neuralgia  and  neuritis  and  consists 
of  prodigiosus  organisms  and  staphylococci  which  have  been  permitted 
to  autolyze. 

Danysz'  method  of  treating  disease  has  been  discussed  in  full  in  a  recent 
number  of  the  Bulletin  medicate.  He  describes  anew  the  technic  and  his 
experience  in  352  cases  since  1913.  In  seeking  for  an  efficient  antiana- 
phylactic,  he  started  from  the  theory  that  the  focus  of  production  of  the 
substances  generating  the  anaphylaxis  in  the  majority,  if  not  in  all,  of  the 
chronic,  noncontagious  diseases,  is  in  the  bowel:  The  albuminoid  matters 
or  microbian  contents  of  the  intestinal  canal  passing  into  the  blood  through 
the  congested  intestinal  mucosa  act  as  antigens  and  induce  the  anaphylactic 
state  of  the  organism.  Consequently,  he  reasoned,  the  microbes  isolated 
from  the  intestinal  contents  ought  to  act  as  antigens  when  inoculated  or 
ingested.  The  microbes  are  isolated  from  a  scrap  of  stool  by  sowing  on 
ordinary  culture  bouillon  and  then  making  pure  cultures  on  gelose,  and 
then  mixing  the  cultures  in  the  same  proportions  as  found  originally. 
This  is  diluted  with  physiologic  serum,  sterilized  with  heat  and  the  dose 
determined  by  weight.  For  ingestion,  the  dose  is  1/10  to  5/10  mg.  of  the 
microbian  bodies;  for  injection  1/1,000  or  1/1,200  mg.  At  first  he  made 
an  autogenous  antigen  for  each  patient,  but  finding  that  the  species  and 


36  PROTEIN  THERAPY 

proportions  of  bacteria  were  so  uniform,  he  used  a  polyvalent  heterogeneous 
preparation  in  some  cases. 

Muck's  Antigen. — Much  has  recently  described  a  vaccine  which 
he  terms  "Immunvollvaccine'  for  intramuscular  injection,  which  he 
has  used  in  the  treatment  of  influenza.  It  is  prepared  from  a  num- 
ber of  nonspecific  antigens:  (a)  Reactive  proteins,  the  metabolic 
products  of  several  nonpathogenic  bacteria,  (b)  a  lipoid  mixture  from 
bile,  and  (c)  a  fat  mixture  of  animal  derivation.  The  theory  under- 
lying such  a  mixture  is  that  of  partial  antigens  which  he  has  developed 
in  tuberculosis. 


BACTERIAL  EXTRACTS  AND  RELATED  SUBSTANCES 

The  use  of  bacterial  extracts  and  of  bacterial  growth  products 
to  produce  a  nonspecific  temperature  increase  is  not  a  recent  inno- 
vation. 

Tuberculins  have  been  used  for  this  purpose  for  some  time,  es- 
pecially in  the  treatment  of  paresis,  as  introduced  by  v.  Jauregg.  For 
this  purpose  a  relatively  large  dose  is  used,  beginning  with  0.01  mg. 
and  increasing  rapidly  until  as  much  as  0.5  mg.  is  injected.  The 
temperature  reaction  is  a  prolonged  one;  usually  a  leukocytosis  is 
produced.  It  offers  no  particular  advantages  over  milk  injections 
which  produce  practically  the  same  results. 

Kaiser  has  used  Tebelon,  the  isobutyl  ester  of  oleic  acid  (intro- 
duced by  Stoeltzner) ,  in  a  number  of  surgical  conditions.  Like  other 
nonspecific  substances  it  acts  as  a  pyrogenic  agent  even  in  nontuber- 
culous  diseases. 

Typhin. — Biedl  in  1915  noted  that  the  nonspecific  reaction  could 
be  elicited  with  histamin,  the  toxicity  of  which  had  been  previously 
studied,  v.  Groer  made  use  of  this  knowledge  in  preparing  a  mix- 
ture of  nucleoprotein  and  histamin  from  typhoid  bacilli  which  he 
called  "typhin"  to  be  used  in  place  of  whole  bacilli  for  intravenous 
injections.  The  chief  advantage  of  the  preparation  lay  in  the  fact 
that  with  such  a  substance  the  dosage  might  be  standardized  and 
the  reaction  gauged.  With  this  "typhin"  v.  Groer  treated  23  cases 
of  typhoid,  of  whom  18  made  a  prompt  recovery  and  5  died.  In 
the  case  of  a  typhoid  patient  that  recovered  by  crisis  after  the  in- 
jection and  died  a  few  days  later  from  an  intercurrent  condition,  v. 
Groer  observed  at  the  autopsy  that  the  ulceration  of  the  bowel  had 
practically  healed  and  that  the  spleen  was  small  (v.  Wiesner  has 
recorded  similar  observations). 

It  is  interesting  to  note  that  v.  Groer  found  no  increase  of  anti- 
bodies in  the  serum  of  patients  after  the  injection  despite  the  fact 
that  such  patients  made  an  excellent  and  prompt  recovery  after  the 
injections. 


THE  NONSPECIFIC  AGENTS  37 

Intramuscular  injections  are  recommended  for  common  use.  He 
also  gave  small  doses  of  digitalis  a  few  days  preceding  the  injection 
in  severely  toxic  cases. 

Coley's  Fluid. — This  consists  of  fluid  culture  products  of  the  strep- 
tococcus and  pyocyaneus.  It  is  used  particularly  in  sarcomata  in 
which  it  was  usually  followed  by  a  severe  systemic  reaction  and  some 
evidence  of  digestion  and  autolysis  of  the  tumor,  but  never  to  the  ex- 
tent of  complete  eradication  of  the  neoplasm. 

Pneumococcus  Autolysate. — Among  bacterial  autoly sates  which 
were  prepared  on  a  specific  basis  but  which  in  all  probability  were 
effective,  when  therapeutically  active,  as  nonspecific  agents  were  the 
pneumococcus  autolysates  of  Rosenow,  recommended  for  use  in  lobar 
pneumonia. 

Phylacogens  (Schafer's  Vaccine.) — These  represented  bacterial 
growth  products  of  a  number  of  bacteria  first  prepared  by  Schafer 
and  used  with  some  success  in  arthritis.  They  were  later  prepared  on 
a  commercial  scale  and  marketed  under  the  trade  name  of 
Phylacogens.  Inasmuch  as  the  method  of  preparation  and  exact  com- 
position is  not  known,  the  reaction  merely  a  nonspecific  one,  other 
and  less  expensive  agents  will  be  found  more  satisfactory  and  more 
easily  controlled. 

COLLOIDAL  METALS 

Colloidal  metals  were  perhaps  first  used  as  therapeutic  agents  by 
Crede  in  1895.  Crede  used  silver  preparations  on  the  assumption 
that  they  were  actively  streptococcocidal,  and  they  were  introduced 
by  him  in  the  treatment  of  streptococcus  infections.  The  range  of 
application  was,  however,  soon  extended  to  septic  conditions  in  gen- 
eral (it  was  no  longer  considered  a  specific  streptococcicide  but  to  pos- 
sess heterobactericidal  properties)  and  latterly  it  has  been  surmised 
that  its  usefulness  depended  not  on  its  particular  chemical  structure 
but  on  properties  of  colloidal  metals  in  general  which  produced 
the  nonspecific  reaction  and  were  therefore  typical  ergotropic  agents. 
Earlier  workers  had  followed  Crede  in  the  interpretation  of  the  method 
of  action  (Marquis  dos  Santos  and  Alphonse  Pinto) ;  Albrecht  sur- 
mised that  the  catalytic  property  of  the  finely  dispersed  metals 
might  have  a  definite  relation  to  the  therapeutic  effect;  while  later 
the  reactive  leukocytosis  that  followed  the  injections  was  studied 
and  held  responsible  for  the  therapeutic  result.  (Dunger,  Sahli,  Bruntz 
and  Spillmann.) 

Bonnaire  and  Kausch  both  noted  and  emphasized  the  important 
fact  that  following  the  intravenous  injection  a  chill,  fever  and  leu- 
kocytosis were  commonly  observed.  This  febrile  reaction,  just  as 
in  other  nonspecific  reactions,  varies  considerably  with  the  disease 
process.  In  sepsis  Kausch  noted  that  the  high  temperature  dropped 
promptly  by  lysis,  whereas  afebrile  cases,  such  as  carcinoma,  responded 


38  PROTEIN  THERAPY 

with  a  sharp  febrile  rise.  Eberstadt  in  treating  erysipelas  did  not 
observe  any  initial  rise  in  temperature  following  the  injection;  a 
lysis  occurred  in  his  four  cases. 

The  fact  that  colloidal  metals  are  active  catalytic  agents  has 
led  to  the  theory  that  in  the  organism  they  act  therapeutically  by 
virtue  of  this  property  as  inorganic  ferments.  Vergely  in  a  recent 
review  calls  attention  to  this  effect  in  connection  with  the  enormous 
surface  developed  by  colloidal  preparations  of  this  type.  A  liter 
of  a  0.5  per  thousand  solution  of  colloidal  gold,  for  example,  presents 
a  surface  of  150,000  square  centimeters,  while  the  same  weight  of 
gold  in  a  compact  form  presents  a  surface  of  only  50  square  milli- 
meters. In  therapeutics,  they  whip  up  the  organism  but  if  it  is  unable 
to  respond,  they  can  do  no  good.  If  the  patient  is  unable  to  produce 
more  leukocytes,  there  is  no  chance  of  success.  In  selecting  the 
colloid  to  use,  he  advises  the  metal  that  has  been  found  most  active 
against  the  bacteria,  etc.,  involved.  He  adds  that  injection  of  a  col- 
loid may  favor  the  production  of  a  fixation  abscess  when  this  is 
attempted  at  the  same  time.  There  is  a  place  for  colloidal  thera- 
peutics, he  concludes,  besides  vaccine  therapy  and  serotherapy,  but 
its  principal  indication  is  in  chronic  disease  or  infection. 

While  the  reaction  that  follows  the  injection  of  colloidal  metals 
may  be  quite  severe,  relatively  few  untoward  effects  have  so  far  been 
reported  in  the  medical  press.  Eyth  and  Moser  have  reported  deaths; 
Saito,  Eberstadt,  Kausch  and  Werler  have  reported  severe  shock  re- 
actions. Injections  must  be  made  very  slowly;  therapeutic  results 
can  be  expected  only  when  the  metals  are  given  early  in  the  dis- 
ease process. 

A  variety  of  colloidal  metals  have  been  prepared  for  therapeutic 
use,  some  of  which  are  on  the  market  as  commercial  preparations. 
The  colloidal  silver-albumen  preparations  have  been  used  longest. 
Arsenic,  iodin,  manganese-copper  and  platinum,  zinc,  manganese, 
gold,  iron,  sulphur,  mercury,  tin  oxid,  etc.,  have  been  used  with  vary- 
ing success.  The  dosage  depends  of  course  on  the  amount  of  metal 
dispersed  in  the  solution  and  on  the  degree  of  reaction  produced, 
both  variable  factors,  that  require  a  certain  amount  of  trial  for  each 
preparation.  The  treatise  of  Searle  covers  the  field  of  recent  English 
work  with  colloidal  metals. 

Of  the  silver  preparation  the  dosage  has  varied  in  practice  from 
the  minute  doses  given  by  Gellhaus,  who  used  fractions  of  a  cubic 
centimeter,  to  those  of  Kausch,  who  commonly  injected  from  10  to 
25  c.c.  and  even  gave  as  much  as  100  c.c.  of  a  2%  solution  intra- 
venously. 

The  colloidal  metals  are  given  not  only  intravenously  and  sub- 
cutaneously,  but  have  been  used  locally,  given  per  os  and  even  as 
clysma.  Alexander,  for  instance,  gives  first  one  injection  intrave- 
nously (10  c.c.  of  a  2%  solution),  then  follows  the  next  day  with  a 


THE  NONSPECIFIC  AGENTS  39 

clysma  of  50  c.c.  of  a  5%  solution.  K.  and  R.  Klotz  have  used  it  in 
the  form  of  a  clysma,  giving  1  mg.  daily  during  the  course  of  pneu- 
monia. 

The  question  arises  in  connection  with  the  injection  of  these  metallic 
preparations  how  much  of  the  reaction,  and  consequently  of  the  thera- 
peutic benefit,  is  due  to  the  dispersed  metal  and  how  much  to  the  protective 
colloid  that  the  manufacturer  adds  to  his  solution  to  make  it  stable.  Thus 
for  the  commercial  iodo-collargol  preparation  the  composition  is  stated 
by  the  manufacturer  to  be  31%  in  silver,  37%  iodin  and  31%  protective 
colloid.  Other  preparations  vary  in  the  amount  of  protective  colloid  added 
and  the  substances  used  for  this  purpose. 

Auld  has  published  some  illuminating  experiences  in  this  connection. 
He  had  been  working  with  colloidal  platinum  solutions  for  several  years 
and  found  one  particular  preparation  very  effective  therapeutically.  This 
was  an  old  solution  that  had  been  in  his  laboratory  for  some  time.  Intra- 
venous injections  of  from  3  to  7  c.c.  resulted  invariably  in  a  sharp  reac- 
tion on  the  part  of  the  patient — a  chill  commencing  in  about  half  an  hour, 
the  temperature  rising  to  104°  F.  and  105°  F.  and  the  patient  complaining 
of  nausea  and  headache.  This  reaction  occurred  both  in  normal  individuals 
and  in  patients  suffering  from  a  variety  of  ailments.  His  othei  platinum 
preparations  did  not  give  this  sharp  reaction  and  the  therapeutic  effect 
likewise  was  lacking.  On  further  investigation  of  the  matter  Auld  ascer- 
tained from  the  manufacturers  that  this  particular  preparation  had  been 
stabilized  by  a  solution  of  veal  peptone  (0.4%)  together  with  1%  glucose. 
This  peptone  on  trial  gave  an  identical  reaction  on  the  part  of  the  patient 
as  the  original  platinum  solution  and  could  be  used  therapeutically  with 
equal  success. 

The  use  of  the  colloidal  metals  has  been  very  extensive  in  a 
variety  of  clinical  fields,  both  for  septic  conditions  as  well  as  in 
certain  special  conditions  such  as  skin  diseases,  venereal  diseases, 
etc.  Thus  Reichmann  has  obtained  good  results  in  sepsis,  endocarditis 
and  rheumatism;  Bichon  in  rheumatic  iritis;  Salomon,  and  Labbe 
and  Moussaud  (colloidal  gold)  in  typhoid;  Richter  in  trench  fever; 
Klewitz  in  endocarditis.  A  number  of  general  articles  covering  .the 
subject  have  been  published  which  will  be  found  of  interest:  Guaita, 
Meyer,  Kausch,  Bockemueller,  Cowadias,  Loeper  and  Wahram, 
Laumonier,  etc. 

It  has  been  found  that  after  the  injection  the  colloidal  metal  is 
deposited  chiefly  in  the  liver,  the  spleen  and  the  bone  marrow  (Voight) . 
A  separate  field  for  therapeutic  application  of  the  colloidal  metals 
lies  in  their  use  as  adjuvant  agents  in  radiotherapy.  In  this  connec- 
tion considerable  progress  has  been  made  in  recent  years. 

The  colloidal  metals,  like  many  of  the  other  nonspecific  agents, 
are  as  a  rule  less  active  on  reinjection.  Bottner,  however,  believes 
that  he  has  been  able  to  demonstrate  that  the  organism  may  be  sen- 
sitized to  collargol  and  that  on  reinjection  in  proper  time  intervals, 
the  patient  will  react  more  strongly  than  with  the  first  injection. 


40  PROTEIN  THERAPY 

This  has  a  definite  value  in  such  conditions  as  arthritis  where  a 
sharp  reaction  on  the  part  of  the  patient  is  usually  very  desirable. 

MISCELLANEOUS 

Hypertonic  and  Hypotonic  Salt  Solutions.— The  injection  of  large 
intravenous  doses  of  salt  solution  in  the  treatment  of  typhoid 
fever  dates  from  the  report  of  Englander.  Englander  while  treating 
a  case  of  typhoid  that  had  had  a  severe  hemorrhage  injected  some 
300  c.c.  of  normal  saline  intravenously.  This  was  followed  shortly 
after  the  injection  by  a  severe  chill,  and  the  usual  nonspecific  re- 
action. The  following  day  the  temperature  declined  to  35.2°  C.  (95.4° 
F.),  and  the  patient  made  a  prompt  recovery  by  lysis  that  commenced 
the  day  following  the  injection.  Other  cases  were  then  treated  by 
Englander  with  the  same  method. 

Sodium  chlorid  cannot,  however,  in  the  light  of  our  present 
knowledge  be  considered  as  an  indifferent  substance  to  the  organism. 
The  observation  of  Hutinel  that  salt  causes  fever  even  when  injected 
in  infants  in  small  doses  has  been  the  subject  of  considerable  dis- 
cussion, Samelson  contending  that  such  temperature  disturbance  was 
due  to  the  fact  that  impurities  were  injected  with  the  salt  or  in  the 
water  used  in  making  up  the  salt  solution.  Bendix  and  Bergmann 
came  to  the  same  conclusion.  More  recent  observations  concerning 
the  role  of  the  sodium  ion  in  its  relation  to  the  permeability  of  cell 
membranes,  and  the  role  of  the  water  content  of  the  tissues  in  the 
mechanism  of  fever  leave  the  status  somewhat  uncertain. 

Instead  of  using  large  doses  and  producing  a  marked  reaction 
in  the  patient  as  Englander  did,  Danielopolu  has  used  repeated  small 
doses  of  hypotonic  salt  solution  (.065)  in  the  treatment  of  typhus 
fever.  By  this  method  he  claims  to  have  obtained  remarkable  re- 
sults. 

Two  other  methods  have  been  devised  in  which  salt  solutions  are 
used,  both  for  local  injection.  Eisel  has  injected  from  10  to  15  c.c. 
of  physiological  salt  solution  locally  between  the  scrotum  and  tunica 
vaginalis  in  cases  of  epididymitis.  It  is  said  to  be  followed  by  a 
diminution  of  pain  and  hastening  of  resorption. 

The  production  of  salt  abscesses  is  another  method  recently  de- 
vised, but  one  that  cannot  be  recommended.  This  is  produced  by 
injecting  a  (5  to  8  c.c.)  concentrated  solution  of  salt  intramuscularly 
(30  parts  sodium  chlorid,  1  part  calcium  chlorid,  100  parts  water) 
and  was  recommended  by  v.  Szily  and  Stransky.  Needless  to  state, 
in  this  case  an  abscess  usually  forms  and  from  it  autolytic  products 
are  absorbed;  as  Luithlin  has  pointed  out,  it  is  merely  a  form  of  the 
older  "fixation  abscess"  of  Fochier  with  the  disadvantage  that  the 
method  is  very  painful  and  leads  frequently  to  complications.  Raege 
and  Zieler,  who  have  both  used  the  method,  condemn  it. 


THE  NONSPECIFIC  AGENTS  41 

Sugar  Solutions. — The  use  of  sugar  solutions  (usually  glucose)  for 
intravenous  injections  in  sepsis,  in  pneumonia  and  other  infectious 
diseases  has  been  repeatedly  reported,  with  some  evidence  of  clini- 
cal usefulness.  There  is  usually  a  slight  temperature  reaction  fol- 
lowing the  injection  and  a  leukocytosis  of  from  5,000  to  20,000. 
Audain  and  Masmonteil  inject  from  500  to  2,000  c.c.  daily  and  re- 
port satisfactory  results  in  sepsis,  erysipelas  and  rheumatism.  The 
isotonic  solutions  are  made  up  as  follows:  For  glucose  47.6  p.m.,  for 
saccharose  103.5  p.m.,  for  lactose  108.9  p.m. 

The  use  of  sugar  injections  in  the  treatment  of  tuberculosis  led 
Hasenbein  to  suggest  sugar  injections  to  produce  focal  reactions  in 
general.  He  used  a  50%  solution  of  cane  sugar  in  doses  of  from  3 
to  5  c.c.  to  which  was  added  1  c.c.  of  a  2%  solution  of  novocain  (in- 
tramuscular injection).  In  females  suffering  from  gonorrhea  there 
was  a  typical  focal  reaction  with  first  an  increased  secretion,  fol- 
lowed later  by  a  diminution. 

Distilled  Water.— Reactions  have  been  reported  from  distilled 
water  when  injected  in  relatively  large  amounts  intravenously. 

Formalin. —  Torry,  working  with  acute  and  chronic  rheumatism, 
has  injected  formaldehyd  intravenously  to  produce  the  shock  re- 
action. The  toxic  agent  which  brings  about  the  reaction  according  to 
Torry  is  probably  a  formaldehyd-protein  compound.  The  dosage 
is  as  follows:  Formalin  is  used  (37%  solution  of  formaldehyd)  and 
of  this  from  1.5  to  3  c.c.  are  injected  after  diluting  in  from  200  to  300 
c.c.  of  physiological  salt  solution. 

During  the  administration  there  is  some  bronchial  irritation  and 
lacrimation.  After  the  injection  a  typical  protein  shock  reaction 
occurs  in  about  half  an  hour's  time,  i.e.,  chill,  fever,  sweating,  etc. 

Solusin.— From  Szily's  laboratory  another  chemical  mixture  has 
been  published,  interesting  rather  than  useful.  This  consists  of  1.4 
parts  of  bichlorid  of  mercury,  0.5  part  sodium  arsenate,  24  parts  of 
sodium  iodid  and  distilled  water  100  parts.  Of  this  mixture  from 
1  to  2  c.c.  are  injected  and  the  patient  is  said  to  react  with  a  typical 
chill,  fever,  sweating,  etc.  Ammoniacal  copper  sulphate  in  a  4% 
solution  has  been  used  by  Noire  for  intravenous  injection  in  puerperal 
infections. 

Hetol,  the  sodium  salt  of  cinnamic  acid,  Sodium  Succinate,  Suc- 
cinimid,  Levurine  and  Tyimarin,  Formic  Acid  (Krull) ,  to  mention  but 
a  few  of  the  drugs  that  have  been  used  as  nonspecific  stimulants,  are 
all  characterized  by  a  leukocytosis  following  their  injection. 

The  use  of  the  active  toxic  agent  of  Bee  stings  and  Snake  Venom 
has  been  reported  for  a  number  of  diseases,  the  former  with  par- 
ticular success  by  Terc  and  Langer  in  the  treatment  of  arthritis. 

lodids.— A  discussion  of  the  probable  mechanism  of  the  therapeutic 
effect  of  the  iodids  might  be  of  value  in  this  connection,  but  inasmuch  as 


42  PROTEIN  THERAPY 

the  subject  should  be  treated  together  with  a  number  of  related  chemical 
problems  in  an  extended  manner,  the  present  treatise  will  not  offer  a  suitable 
opportunity.  Jobling  and  Petersen  have  discussed  some  of  the  features 
in  a  paper  published  in  the  Archives  of  Internal  Medicine,  where  the  litera- 
ture will  be  found.  It  seems  very  probable  that  the  iodids  play  a  con- 
siderable role  in  the  stimulation  of  tissue,  particularly  in  the  enzyme 
phenomena.  Sherrick's  and  Sollmann's  interesting  observations  on  the 
alteration  of  the  reactivity  of  the  skin  to  cutaneous  injections,  the  reaction 
of  tuberculous  patients  (Petersen)  and  of  carcinoma  patients  (Moresowa) 
are  but  a  few  instances  of  this  effect.  The  property  of  the  iodids  in  in- 
creasing the  rate  of  diffusion  of  a  number  of  substances  in  colloidal  systems 
evidently  is  closely  related  to  their  therapeutic  effect. 

Turpentine. — The  use  of  turpentine  for  subcutaneous  injections  is 
an  old  procedure  that  in  a  modified  form  has  been  very  recently  re- 
introdnced  in  the  treatment  of  skin  diseases  and  inflammatory  con- 
ditions. Fochier  in  the  early  nineties  had  introduced  the  "Fixation 
Abscess"  as  it  was  termed,  produced  by  injecting  about  1  c.c.  of  tur- 
pentine subcutaneously  and  intramuscularly.  The  abscess  was  used 
in  certain  acute  infections,  including  pneumonia,  puerperal  fevers, 
adnexal  inflammation,  etc.  In  many  ways  this  was  merely  the  re- 
introduction  of  the  very  ancient  method  of  producing  an  "issue" 
by  the  use  of  seton  or  fontanelle. 

More  recently  the  French  and  German  clinicians  have  modified 
this  method  and  are  now  injecting  minute  quantities  of  turpentine 
(20%  of  turpentine  in  olive  oil)  intramuscularly  in  frequently  re- 
peated doses.  The  mechanism  involved  is  merely  the  production  of  a 
multitude  of  small  sterile  areas  of  inflammation  and  necrosis,  with 
tissue  stimulation  from  these  foci.  It  is  said  to  be  used  with  suc- 
cess in  a  number  of  skin  diseases  and  the  French  observers  have 
used  it  extensively  in  the  treatment  of  influenzal  pneumonia,  etc. 

According  to  Karo  the  turpentine  mixture  in  olive  oil — 4  parts  in 
16  parts  of  olive  oil — is  borne  much  better  if  one  adds  a  sedative 
such  as  eukupine.  This  lessens  the  pain  at  the  site  of  injection. 
Naturally  care  must  be  taken  to  avoid  the  subcutaneous  tissues  and 
inject  wholly  intramuscularly. 

Karo  has  more  recently  recommended  the  use  of  "Terpichin." 
This  is  absolutely  free  from  rosins  and  oxids  and  is  combined  with 
quinin  which  seems  to  increase  its  activity.  The  injections  which 
are  similar  to  those  of  turpentine — intragluteal  and  usually  biweekly 
— are  followed  by  a  well  marked  general  stimulation  of  the  patient  as 
well  as  a  leukocytosis. 

Antipyretics. — The  nonspecific  effect — plasmaactivation — that  re- 
sults from  the  use  of  certain  drugs  has  recently  been  studied  by 
Koniger.  He  has  come  to  the  conclusion  that  the  antipyretics  have 
such  an  effect  quite  apart  from  the  usual  pharmacological  effect  here- 
tofore studied,  an  effect  which  can  be  demonstrated  if  the  dosage 


THE  NONSPECIFIC  AGENTS  43 

is  given  in  proper  intervals.  The  effect  is  diphasic,  as  with  all  other 
nonspecific  agents. 

Yeast. — The  use  of  yeast  is  an  ancient  one  in  therapy.  Hippocrates 
is  supposed  to  have  applied  it  in  the  treatment  of  leukorrhea;  during 
the  Middle  Ages  it  is  said  to  have  been  prescribed  in  plague;  it  was 
not  until  the  middle  of  the  last  century,  however,  that  it  was  used 
on  a  larger  scale  (Mosse)  and  since  then  its  popularity  has  gone 
through  several  cycles  of  advance  and  of  decline.  In  furunculosis, 
in  anthrax,  in  diabetes,  in  suppurative  processes,  in  diseases  of  the 
gastro-intestinal  tract,  in  arthritis,  and  in  sepsis  it  found  many  ad- 
herents during  the  earlier  revival  but  by  the  end  of  the  century 
it  had  again  practically  vanished  as  a  therapeutic  measure.  Brocq 
revived  its  use  in  1899.  In  the  period  from  1900  to  1907  a  great 
number  of  clinical  reports  were  published,  together  with  some  ex- 
perimental data  (Lardier,  Krause,  Hedrich) ;  more  recently  Hawk 
and  his  associates  have  published  a  series  of  cases,  chiefly  acne,  (vul- 
garis  and  rosacea)  and  furunculosis,  in  which  excellent  results  were 
obtained  by  yeast  therapy.  Besides  the  skin  diseases,  Hawk  and 
his  coworkers  reported  favorable  results  in  acute  bronchitis,  urethritis, 
conjunctivitis,  arthritis  deformans,  etc.  In  all  of  these  conditions  it 
is  reported  that,  apart  from  any  influence  on  the  local  pathological  con- 
dition, the  general  nutrition  of  the  patient  was  improved.  Even  when 
given  via  the  intestinal  tract  there  is  evidence  of  a  stimulating  ef- 
fect of  the  yeast  in  the  leukocytosis  which  is  demonstrable  after  its 
use. 

Recently  Wolf  and  Lewis  have  endeavored  to  establish  some  basis 
for  the  therapeutic  use  of  yeast  by  investigating  whether  the  inges- 
tion  of  yeast  would  in  any  way  influence  the  antibody  titer  of  the  serum 
of  experimental  animals.  Their  results  were  negative. 

Light  Rays — Roentgen  Rays — Radium — Photodynamic  Agents. — 
These  agents  may  in  some  measure  bring  about  a  systematic  re- 
action on  the  part  of  the  patient,  depending  on  the  dosage,  the  organ 
or  the  pathological  tissue  irradiated  and  the  amount  of  necrosis  already 
present  or  produced  by  the  agents  under  consideration.  All  these 
agents  first  stimulate  tissue  cells,  later  with  prolonged  exposure, 
cause  the  death  of  the  cell.  In  both  cases  substances  enter  the  blood 
stream  that  cause  a  general  reaction  on  the  part  of  the  patient;  this 
may  be  mild  in  character,  may  cause  a  severe  febrile  reaction,  or  even 
complete  shock  with  lowered  blood  pressure,  prostration,  and  even 
death.  After  the  moderate  reactions  of  this  type,  if  the  patient  is  in 
fairly  good  condition  and  able  to  respond,  a  definite  euphoria,  an  im- 
provement of  the  appetite,  nutrition  and  general  well-being  may  set 
in,  just  as  after  other  nonspecific  agents. 

In  this  category  must  be  placed  the  effect  of  heliotherapy  in  the 
treatment  of  tuberculosis  and  other  chronic  infections,  the  effect  of 


44  PROTEIN  THERAPY 

remote  Roentgen  irradiation  on  asthma  (Schilling-Drey  and  Losser, 
etc.),  on  the  hastening  of  ossification  (Stettner),  on  furunculosis 
(Schrews),  on  local  inflammatory  processes  (Kaznelson  and  St.  Lo- 
rent) ,  the  effect  of  radium  on  arthritis,  gout,  adnexal  inflammation,  etc. 
(Gudzent) . 

The  shock  following  actual  burns  or  that  following  the  effect  of 
photodynamic  agents  such  as  those  introduced  and  studied  by  von 
Tappeiner,  has  its  place  in  this  same  category.  (Pfeiffer.) 

Biological  Alterations. — As  will  be  pointed  out  more  fully  in  the 
chapter  on  The  Focal  Reaction,  it  is  very  probable  that  a  variety  of 
alterations  in  the  organism  may  bring  about  effects  on  pathological 
processes  similar  to  those  that  we  induce  artifically  with  nonspecific 
injections.  The  menstrual  cycle  and  pregnancy,  chilling,  prolonged 
exercise,  intoxication  arising  from  faulty  gastrointestinal  absorption, 
starvation,  even  endocrine  disturbance  and  the  effect  of  nervous  excita- 
tion must  be  considered  from  this  point  of  view. 

In  a  like  manner  the  products  of  an  inflammatory  reaction  in  one 
tissue  may  bring  about  a  nonspecific  reaction  of  the  entire  organism 
and  so  alter  pathological  processes  elsewhere.  A  number  of  dermatol- 
ogists have  called  attention  to  this  possibility  in  connection  with  the 
clinical  observation  that  in  extensive  luetic  or  tuberculous  lesions  of 
the  skin  the  internal  organs  are  apt  to  be  relatively  free  from  dis- 
ease. The  discussion  of  these  problems  will  be  taken  up  in  a  later 
chapter. 

Depression  Immunity. — Even  acute  diseases  are  profoundly  altered  by 
shock  effects  due  to  intercurrent  conditions.  Thus  the  malarial  paroxysm 
will  in  the  typhoid  patient  frequently  bring  about  either  a  temporary  or 
permanent  detoxication  (Zupnik,  v.  Miiller  and  Leiner),  and  v.  Jauregg 
has  even  inoculated  patients  with  malarial  plasmodia  (in  cases  of  paresis) 
as  a  therapeutic  measure.  The  acceleration  of  wound  healing  after  ery- 
sipelas (Goebel),  or  the  effect  of  erysipelas  on  tumor  growth,  the  effect 
of  pregnancy  on  tumor  growth  (Slye)  are  all  related  phenomena.  Morgen- 
roth,  Biberstein  and  Schnitzer  have  recently  studied  immunity  conditions 
bearing  on  this  problem  which  can  only  briefly  be  outlined  at  this  time. 
They  have  been  experimenting  with  superinfection  or  superimposed  infec- 
tion, as  this  field  of  investigation  has  thus  far  resisted  any  attempts  to 
harmonize  its  findings  with  the  prevailing  theories  in  regard  to  immunity, 
and  as  experimental  studies  in  this  field  seemed  to  promise  good  results. 
They  started  with  the  commonly  accepted  theory  that  the  infected  organism 
acquires  an  immunity  against  superinfection,  and  against  a  like,  super- 
imposed infection,  but  they  became  interested  in  the  investigations  of  Land- 
steiner  and  Finger,  who  maintain  that  the  organism  infected  with  syphilis 
is  by  no  means  immune  to  a  new  syphilitic  infection,  as  has  been  commonly 
supposed.  Their  experiments  demonstrated  that  mice  with  an  experi- 
mental, chronic  streptococcus  infection,  streptococci  being  found  in  the 
blood  and  in  the  organs,  possess  immunity  toward  a  superinfection  with 


THE  NONSPECIFIC  AGENTS  45 

streptococci,  as  is  shown  by  the  fact  that  when  given  a  streptococcus  dose, 
such  as  will  kill  normal  animals  within  twenty-four  hours,  they  show  no 
change  in  their  behavior.  They  are  immune  not  only  toward  the  strain 
of  streptococcus  with  which  they  were  primarily  infected  but  also  against 
foreign  strains  of  streptococcus.  However,  this  immunity  is  not  absolute 
but  relative,  for  it  is  broken  down  by  a  strain  of  especially  high  virulence, 
in  which  case  the  infection  runs  an  acutely  fatal  course,  as  in  the  controls. 
This  partial  immunity  does  not  lie  in  the  fact  that  the  superinfection  does 
not  "take";  on  the  contrary,  the  streptococci  used  for  the  superinfection 
appear  in  the  blood  and  organs,  and  by  the  aid  of  especially  "marked" 
strains  could  be  shown  to  remain  present  for  some  time.  The  partial  im- 
munity consists,  therefore,  merely  in  a  depression  of  the  virulence  of  the 
infection.  This  immunity  was  developed  in  from  six  to  twenty-four  hours 
after  the  experimental  infection.  It  does  not  seem  to  have  anything  to 
do  with  anaphylaxis,  but  presents  a  new  kind  of  immunity.  They  theorize 
that  the  passing  of  an  acute  infection  into  a  chronic  phase  is  conditioned 
by  the  development  of  this  "depression  immunity."  The  latter  is  not  the 
result  of  the  chronic  infection,  but  every  infection  that  is  not  rapidly  fatal 
has  its  course  determined  by  the  depression  immunity.  Each  phase  of 
the  infection  is  the  result  of  the  antagonism  between  the  causal  germ  and 
the  degree  of  depression  immunity  at  the  moment.  This  assumption  throws 
light  on  natural  immunity  and  all  other  forms  of  immunity  which  do  not 
fit  into  the  picture  of  immunity  from  antibody  production. 

Otto  Wiegand  has  recently  contributed  to  the  same  subject  and  Berliner 
and  Citron  working  with  chicken  cholera  in  guinea-pigs  have  confirmed 
the  findings  of  Morgenroth  and  his  associates. 


CHAPTER  III 
THE  NONSPECIFIC  REACTION 

The  intravenous  injection  of  bacterial  suspensions  such  as  typhoid 
bacilli,  colon  bacilli  or  staphylococci,  their  intramuscular  injection  in 
larger  dosage,  the  intravenous  injection  of  bacterial  or  other  protein 
split  products  such  as  proteoses ;  of  colloidal  metals ;  of  distilled  water 
or  hypertonic  salt  solution ;  of  various  serums  and  antitoxins ;  the  intra- 
muscular injection  of  milk  or  casein,  the  subcutaneous  injection  of 
nucleic  acid  or  sodium  nucleate,  the  production  of  sterile  abscesses 
with  minute  injections  of  turpentine,  are  all  followed  by  a  reaction 
that  varies  from  a  mere  stimulation  of  leukocytes,  to  mild  febrile 
reactions,  and  to  extreme  shock  pictures  associated  with  profound 
vasomotor  paralyses.  The  reaction  varies  with  the  substance  used, 
its  method  of  application  and  absorption,  and  its  dosage;  with  the 
type  of  infection  with  which  we  are  dealing;  with  the  number  of 
previous  injections;  with  the  physical  condition  of  the  patient;  with 
the  duration  of  the  disease  from  which  the  patient  is  suffering;  with 
the  temperature  of  the  patient  at  the  time  of  the  injection  and  other 
individual  factors. 

We  do  not  yet  know  how  much  of  the  reaction  that  we  elicit 
is  necessary  to  bring  about  the  therapeutic  effect  that  we  seek  to 
achieve.  We  know  that  some  substances  provoke  fewer  symptoms 
that  are  uncomfortable  to  the  patient  and  yet  seem  quite  as  efficacious 
in  their  result.  On  the  other  hand  some  substances  are  followed 
with  only  a  mild  reaction  and  seem  much  less  effective  than  the 
methods  that  are  seemingly  more  drastic  in  their  action  and  much 
more  unpleasant  for  the  patient. 

Certain  of  the  agents  always  give  a  reaction  in  both  normal  in- 
dividuals and  persons  ill  from  disease  and  give  a  reaction  in  a  rela- 
tively short  period  of  time  after  the  injection.  Typhoid  vaccine 
belongs  in  this  category.  The  colon  bacillus  more  often  gives  a  de- 
layed reaction,  while  some  of  the  protein  split  products  such  as  the 
albumoses  may  produce  a  reaction  in  diseased  individuals  but  not  in 
a  normal  person  when  the  same  dosage  is  employed. 

Holler,  while  working  with  deutero-albumose  in  patients,  tried  its  effect 
on  himself  over  a  period  of  over  two  weeks.  In  patients  the  intravenous  in- 
jection of  1  c.c.  of  a  10%  solution  was  invariably  followed  by  a  slight  drop, 
then  a  rise  in  temperature  of  from  2 — 3°  C.,  a  chill,  occasionally  sweating,  rarely 

46 


THE  NONSPECIFIC  REACTION  47 

an  urticaria,  etc.    When  he  injected  it  in  himself  these  symptoms  were  entirely 
lacking.     He  gained  in  weight  during  the  course  of  the  injections. 

This  in  general  has  been  our  experience  in  normal  individuals  when  we  have 
injected  small  doses  of  secondary  proteoses  intravenously.  The  reaction  on 
the  part  of  the  patient  depends  to  a  considerable  degree  on  the  amount  of 
bacterial  destruction  that  follows  the  injection  or  the  amount  of  necrotic  tissue 
involvement  of  the  patient. 

Just  how  much  of  the  nonspecific  reaction  is  essential,  whether 
the  discomfort  of  the  intravenous  bacteriotherapy  can  be  modified  by 
using  the  protein  split  products  without  sacrificing  any  of  the  remark- 
able therapeutic  effects  that  are  at  times  achieved,  is  not  to  be  de- 
termined at  present  but  must  be  the  subject  of  further  clinical  investi- 
gation. For  purposes  of  orientation  we  have  in  the  following  pages 
described  the  reaction  that  follows  the  intravenous  injection  of  typhoid 
bacilli  in  moderate  dosage — 25  to  50  million  organisms;  not  because 
it  may  be  the  ideal  form  of  therapy  of  this  type  but  because  it  is 
the  reaction  which  is  most  familiar  clinically  and,  because  of  the 
availability  of  the  vaccine,  the  most  easily  obtained  agent  for  ex- 
perimentation. 

It  is  practically  impossible  to  ascertain  beforehand,  because  of 
the  varying  individual  factors,  the  degree  of  the  reaction  that  will 
be  produced.  When,  however,  experience  has  been  gained  with  a 
definite  preparation  and  with  a  certain  class  of  clinical  material 
it  is  usually  possible  to  gauge  the  results  that  are  to  be  expected 
with  some  measure  of  exactitude.  Needless  to  state  it  is  an  elemental 
precaution  to  begin  with  a  small  dose  when  undertaking  a  study  of 
the  effect  on  patients. 

The  Chill. — Usually  the  first  symptom  that  comes  to  the  attention 
of  the  patient  following  the  injection  is  a  chill  or  rigor.  This  may  set  in 
as  early  as  fifteen  minutes  after  the  intravenous  injection  of  typhoid 
bacilli  or  a  proteose  solution,  usually  within  30  minutes,  but  may 
be  delayed  for  several  hours.  When  colon  bacilli  and  some  other 
organisms  are  used  the  chill  may  not  be  observed  for  several  hours, 
in  one  of  our  cases  not  until  8  hours  after  the  injection.  With  intramus- 
cular milk  injections  the  rigor  commences  in  from  two  to  three  hours. 

The  degree  of  the  reaction  varies — there  may  be  merely  twitch- 
ing of  the  leg  or  arm  muscles,  or  the  chill  or  rigor  may  be  quite 
general  and  severe  and  last  from  20  minutes  to  an  hour.  Commonly 
this  phase  of  the  reaction  begins  to  wear  off  in  from  one-half  to 
three-quarters  of  an  hour  after  its  inception. 

During  this  time  the  patient  may  complain  of  actual  sensation  of 
chilling  and  demand  extra  covering  and  hot  water  bottles;  in  other 
cases  there  is  merely  the  muscular  twitching  and  trembling  with- 
out sensory  disturbance.  In  .the  acute  arthritides  this  phase  of 
the  reaction  may  be  of  considerable  discomfort  to  the  patient  be- 
cause of  the  added  motion  and  its  resulting  pain  in  the  involved  joints. 


48  PROTEIN  THERAPY 

The  analgesic  effect  that  follows  shortly  in  the  wake  of  the  chill 
as  a  rule  compensates  for  this  short  period  of  increased  pain. 

The  Temperature  Curve.— The  temperature  reaction  of  the  patient 
varies  greatly  with  the  vaccine  or  protein  used,  and  even  when  one  ad- 
heres to  a  single  agent  such  as  typhoid  vaccine,  differences  in  the  age  of 
the  vaccine,  the  dosage,  the  strain  of  bacilli  and  the  method  of  killing 
the  bacteria  when  the  vaccine  is  prepared,  all  have  a  definite  effect  on 
the  reaction;  and  this  apart  from  the  individual  variation  that  we  meet 
on  the  part  of  the  patient — variations  that  depend,  as  already  men- 
tioned, on  the  disease,  its  duration,  the  previous  temperature,  previous 
injections,  etc. 

With  the  subsidence  of  the  chill  or  during  its  later  stages  the 
temperature  of  the  patient  has  as  a  rule  commenced  to  rise.  In 
typical  arthritic  cases  running  a  febrile  course  of  from  100°  F.  to 
101°  F.  the  injection  of  typhoid  vaccine  will  raise  the  temperature 
to  about  103°  F.  or  104°  F.,  the  maximum  increase  being  recorded 
in  from  three  to  four  hours  after  the  injection.  With  intramuscular 
milk  injections  the  temperature  maximum  may  not  be  reached  until 
six  or  eight  hours  after  the  injection.  As  a  rule  the  defervescence 
is  more  rapid  with  the  intravenous  injections,  but  even  in  the  case 
of  the  milk  injections  the  former  level  is  reached  within  24  hours. 
Subcutaneous  nuclein  injections  are  followed  by  a  febrile  reaction 
that  begins  later  and  recedes  more  slowly  than  observed  with  the 
other  methods. 

Schmidt  has  classified  the  reactions  following  milk  injections  into 
5  groups,  according  to  the  degree  of  febrile  reaction  of  the  patient 
following  a  uniform  amount  of  milk  intramuscularly  injected.  In 
the  first  group  are  the  cases  that  react  with  37°  C.  or  under;  in  the 
second  that  react  with  37°  C.  to  38°  C.  (98.6°-100°  F.) ;  in  the  third 
that  react  with  38°  C.  to  39°  C.  (100°-102°  F.) ;  in  the  fourth  that 
react  with  39°  C.  to  40°  C.  (102°-104°  F.) ;  in  the  fifth  that  react  with 
40°  C.  to  41°  C.  (104°-106°  F.). 

Schmidt  and  Kaznelson  worked  chiefly  with  milk  injections,  using 
10  c.c.  injected  intragluteally.  The  temperature  rise  occurred  usually  in 
from  6  to  8  hours  and  was  at  times  accompanied  by  a  chill  (rather  rare), 
more  often  by  sweating,  and  some  headache.  The  blood  pressure  was  not 
altered.  Herpes  were  seldom  noted.  The  temperature  increase  at  times 
persisted  for  from  24  to  48  hours.  Among  the  five  groups  into  which 
Schmidt  and  Kaznelson  have  classified  their  patients  it  will  be  of  interest  to 
observe  some  of  the  cases  in  the  first  three  groups.  They  are  as  follows : 

Temperature  under  37°  C.,  Group  I    Carcinoma,  4 

(98.6°  F.)    (Normal)  Secondary  Anemia,  1 

Myotonia   (Thomsen's  Disease),  1 
Diabetes,  2 
Influenza,  1 


THE  NONSPECIFIC  REACTION  49 

3Y°  0.  to  38°  C.,  Group  II  Hysteria,  1 

(98.6°-100°  F.)  Achylia,  1 

Icterus,  1 
Acromegaly,  1 
Chlorosis,  1 

Posthemorrhagic  Anemia,  2 
Gonitis,  1 
Polyarthritis,  3 
Chronic  Arthritis,  2 
Carcinoma,  8 
Diabetes,  3 
Cholecystitis,  1 

38°  C.  to  39°  C.,  Group  III  Tuberculosis,  4 

(100°  to  102°  F.)  Gumma,  Liver,  1 

Hemophilia,  1 

It  is  of  peculiar  interest  to  observe  the  relative  resistance  of  the  carci- 
noma cases  of  this  series  to  temperature  response  following  the  injections 
(most  of  these  were  stomach  and  esophageal  cases).  The  reactivity  of  the 
neoplasms  varies  greatly — some  observers  report  rather  violent  reactions; 
others,  such  as  Schmidt,  believe  that  they  are  examples  of  decided  resist- 
ance. It  seems  most  probable  that  the  reaction  depends  largely  on  the 
amount  of  necrosis  present  in  the  tumor,  its  vascularity  and  its  ana- 
tomical position.  Schmidt  correlated  this  relative  resistance  to  the  milk 
injections  with  his  previous  observations  concerning  the  relatively  low 
"Infection  Index"  of  carcinoma  patients  and  their  resistance  to  vaccines. 
Wetzel  believes  that  the  absence  of  a  febrile  reaction  to  parenteral  injection 
of  milk  is  not  constant  enough  to  aid  in  diagnosis,  although  it  is  occasionally 
conspicuous  in  diabetes  and  cancer. 

Schmidt  noticed  that  the  reaction  was  independent  of  the  dosage 
to  a  considerable  degree,  although  after  one  or  more  doses  had  been 
given,  the  reaction  became  less  marked.  It  depended  to  a  large  degree 
on  the  individual,  and  the  type  of  the  disease.  Thus  in  a  normal 
person  one  can  inject  as  much  as  1  c.c.  of  a  10%  solution  of  al- 
bumose  without  appreciable  temperature  reaction  or  constitutional 
effect  of  any  nature.  In  an  arthritic  patient  the  same  injection 
may  raise  the  temperature  two  or  three  degrees;  in  a  typhoid  or 
tuberculous  patient  by  as  much  as  five  degrees  (F.).  On  the  other 
hand,  when  the  same  dose  is  injected  in  a  pneumonic  patient  who 
already  has  a  high  temperature  (let  us  say  103°  F.)  the  tempera- 
ture may  not  be  increased,  or  may  actually  show  a  decline  without 
any  preliminary  increase  after  the  injection. 

Habetin,  using  0.5  gm.  of  sodium  nucleate  subcutaneously  in  a 
series  of  some  60-odd  patients  ill  with  a  variety  of  diseases,  classified 
his  reactions  according  to  the  system  of  Schmidt. 

It  will  be  observed  that  the  most  marked  pyrogenic  effect  is  manifest 
in  diseases  involving  hematopoietic  organs  and  those  in  which  definite 


50 


PROTEIN  THERAPY 


foci  of  pathological  tissue  exist  such  as  sarcoma,  tuberculosis,  etc. 
The  degree  of  febrile  reaction  is  independent  to  a  considerable  de- 
gree of  the  agent  or  the  dosage;  it  depends  on  the  infection  and  the 
state  of  the  patient,  i.e.,  on  an  individual  factor. 


I 

II 

III 

IV 

V 

2 

5 

4 

4 

0 

o 

2 

4 

1 

1 

0 

2 

3 

6 

0 

o 

1 

1 

0 

0 

Multiple  Sclerosis     

o 

3 

3 

1 

0 

Diabetes   

0 

1 

0 

0 

0 

o 

1 

0 

o 

0 

o 

0 

1 

0 

0 

0 

0 

1 

0 

0 

Typhoid    

0 

0 

1 

3 

0 

Pernicious  Anemia  

0 

o 

1 

2 

0 

Chlorosis  

0 

o 

1 

0 

0 

0 

o 

0 

1 

0 

Pyemia   

0 

o 

0 

0 

1 

Endocarditis    , 

0 

o 

o 

o 

1 

Gow,  who  early  employed  heterovaccines,  came  finally  to  the  use 
of  the  colon  vaccine  as  being  most  dependable,  other  vaccines  such 
as  streptococcus,  etc.,  being  followed  by  little  temperature  effect.  He 
noted  the  fact  that  the  reaction  varies  greatly  in  different  individuals, 
just  as  had  Schmidt.  A  dose  of  50  million  might  in  one  instance 
cause  a  severe  reaction  but  little  in  another.  For  therapeutic  result 
Gow  concluded  that  a  moderate  reaction  was  essential. 

That  the  injection  of  bacteria  would  cause  fever  and  that  the  reaction 
depended  to  some  degree  on  the  digestion  of  the  bacteria  was  noted  many 
years  ago.  (Gamaleia.)  Roux  and  Lepine  had  observed  the  pyrogenic  ef- 
fect of  the  other  protein  substances  before  this,  while  Charrin  and  Ruffer 
determined  that  the  pyrogenic  effect  of  the  bacteria  was  thermostable,  that 
is,  they  heated  the  bacterial  emulsions  to  110°  C.  and  were  still  able  to 
get  the  original  pyrogenic  effect  on  injection. 

The  later  studies  of  Buchner,  Schittenhelm  and  Weichardt,  of  Fried- 
berger,  Vaughan,  etc.,  are  of  course  well  known. 

The  Pulse. — Coincident  with  the  temperature  reaction  the  pulse  is 
almost  invariably  increased  to  some  extent,  usually  about  15  to  30 
beats  per  minute.  With  the  onset  of  the  sweating  the  peripheral  dilata- 
tion brings  this  down  to  almost  the  preinjection  level.  As  a  rule  the 
quality  of  the  pulse  is  not  altered,  and  arrhythmia,  if  present  before- 
hand, is  not  increased.  Cyanosis  is  uncommon ;  I  have  observed  it  only 
once  following  an  injection  of  proteoses  in  a  case  of  typhoid  fever.  In 
this  case  the  cyanosis  was  a  transient  phenomenon  and  the  patient 


THE  NONSPECIFIC  REACTION  51 

went  on  to  a  complete  recovery  from  his  typhoid  in  two  days. 
Cyanosis  is  but  infrequently  noted  in  the  literature.  Gow  has  re- 
cently studied  the  pulse  rate  in  patients  receiving  peptone  injec- 
tions intravenously.  He  finds  that  the  higher  the  leukocytosis,  the 
greater  the  rise  in  pulse  frequency  after  injections.  The  increase  in 
pulse  rate  in  his  cases  varied  from  5  to  20  beats  per  quarter  minute. 
The  pulse  frequency  returned  to  normal  in  from  3  to  5  minutes  after 
the  injections.  With  vaccines  these  effects  are  of  course  greatly  delayed. 

The  character  of  the  pulse  and  its  rate  is  of  decided  importance  in  de- 
termining which  cases  are  suitable  for  injection.  In  typhoid  a  rapid  pulse 
rate  (over  100)  is  a  contraindication  to  nonspecific  therapy.  Experimen- 
tally it  has  been  shown  that  small  doses  of  proteoses  stimulate  the  heart 
muscle,  the  amplitude  and  the  force  of  the  beat  being  increased  (Weichardt). 
In  several  cases  of  long-standing  heart  lesions  associated  with  arthritis 
we  have  watched  the  size  of  the  heart  after  nonspecific  injections — both 
during  the  acute  reaction  and  the  defervescence.  In  these  cases  the  left 
border  went  out  about  1  cm.  and  returned  to  the  preinjection  size  in  from 
24  to  48  hours.  The  patients  showed  no  evidences  whatever  of  any  cardiac 
decompensation.  Naturally  only  cardiac  patients  that  were  in  good  con- 
dition were  selected  for  the  injections. 

The  Blood  Pressure. — Scully  was  one  of  the  first  to  undertake  sys- 
tematic  studies  on  the  blood  pressure  of  patients  after  typhoid  vaccine 
injections.  It  is  of  course  quite  difficult  to  obtain  an  accurate  reading 
during  the  time  that  the  patient  has  a  chill,  but  enough  observations 
have  been  recorded  to  indicate  that  there  is  a  slight  increase  in  blood 
pressure  during  this  time.  When  the  chill  has  subsided  and  the  period 
of  perspiration  sets  in,  the  blood  pressure  shows  a  progressive  decline 
of  from  10  to  25  mm.,  reaching  a  maximum  in  from  6  to  8  hours, 
and  returning  to  the  normal  pressure  within  24  hours.  Considerable 
variation  is  noted,  however,  in  individual  cases,  depending  on  the 
dosage,  the  agent  used  and  the  infection  of  the  patient.  . 

When  injections  are  given  to  a  typhoid  patient  in  the  later  stages 
of  the  illness,  where  evidence  of  an  unstable  vasomotor  system  fol- 
lowing the  long  continued  toxemia  is  apparent,  we  have  observed  a 
vasomotor  paralysis  extending  over  a  period  of  48  hours  and  very 
refractory  to  stimulation.  In  one  such  case  the  systolic  pressure 
sank  to  55  mm.  and  remained  very  low  for  24  hours.  This  patient 
had  been  running  a  very  high  typhoid  temperature  for  4  weeks  with- 
out any  evidence  of  improvement.  Following  the  recovery  from  the 
injection  his  temperature  remained  normal  and  the  patient  made  a 
complete  recovery. 

A  number  of  factors  enter  into  the  effect  on  the  blood  pressure. 
It  has  been  noted  for  instance  that  the  subcutaneous  injection  of 
relatively  large  doses  of  typhoid  vaccine — Besredka  or  Vincent — 
during  typhoid  fever,  while  it  has  a  much  less  apparent  effect  on 
ftie  patient  in  ftie  form  of  chill,  fever  and  sweating,  seems  to  be 


52  PROTEIN  THERAPY 

followed  by  far  greater  depressing  effects  on  the  cardiovascular 
system  than  the  intravenous  injection  of  small  amounts  of  typhoid 
vaccine.  After  milk  injections  Muller  has  observed  a  slight  primary 
decrease,  then  an  increase  in  the  blood  pressure. 

While  the  effect  on  the  blood  pressure  depends  on  individual  fac- 
tors— the  duration  of  the  disease,  the  agent  used,  etc.,  the  fall  in  the 
blood  pressure  which  accompanies  shock  effects  depends  largely  on 
a  dilatation  of  the  vascular  bed  in  the  splanchnic  area.  The  peripheral 
dilatation  which  one  can  observe  with  the  sweating  of  the  patient  does 
not  produce  the  extreme  drop  in  the  blood  pressure  that  the  splanchnic 
engorgement  does. 

Different  animals  respond  to  the  injection  of  protein  split  products, 
peptone,  histamin,  etc.,  with  different  effects  on  the  blood  pressure,  de- 
pending on  which  part  of  the  vascular  bed  is  subject  to  constriction,  on 
stimulation  of  the  vasomotor  nerves,  etc.  The  liver  of  carnivora  responds 
with  a  spasm  of  the  capillaries  with  a  resulting  diminution  of  the  blood  sup- 
ply to  the  right  heart  and  a  lowering  of  the  blood  pressure.  The  primary  ef- 
fect is  followed  by  a  dilatation.  The  liver  of  the  herbivora  is  quite  in- 
different, indicating  a  difference  in  innervation.  The  spasm  of  the  arteri- 
oles  of  the  portal  area  results  in  a  passive  filling  of  these  vessels  while  in 
the  lungs  we  have  also  a  contraction  of  the  arterial  system  with  a  re- 
sulting dilatation  of  the  right  heart,  accompanied  by  a  fall  in  pressure  in 
the  left  heart  and  the  general  circulation.  In  discussing  this  mechanism 
Mantner  and  Pick  call  attention  to  the  fact  that  the  difference  in  the 
effect  of  the  shock  poisons  in  herbivora  and  carnivora  is  easily  explained  by 
the  differences  in  the  behavior  of  the  various  capillary  systems.  Simonds 
has  recently  noted  this  same  difference  in  the  behavior  of  the  musculature 
of  the  hepatic  vein  and  has  drawn  conclusions  similar  to  those  of  Mantner 
and  Pick.  Dale's  conception  of  the  mechanism  does  not  quite  follow  that 
here  presented. 

It  becomes  apparent  from  a  consideration  of  the  possible  mechanism  in 
the  dog  and  the  human  after  such  shock  effects  why  stimulants  such  as 
adrenalin  are  relatively  ineffective  while  vasodilating  agents  such  as  caffein 
are  said  to  be  followed  by  more  effect  in  the  acute  stage  of  shock  depend- 
ing on  such  vasoconstriction  of  the  hepatic  vein  and  its  branches. 

The  possibility  that  other  factors  enter  into  the  change  in  the  blood 
pressure  is  by  no  means  excluded,  v.  Behring  laid  great  stress  on  the 
finding  of  thrombi  in  the  capillaries  of  the  lungs  in  acute  anaphylactic 
shock  and  Hanzlik  and  Karsner  have  recently  called  attention  to  the  fact 
that  the  intravenous  injection  of  a  number  of  colloids  and  typical  non- 
specific agents  may  be  followed  by  such  changes  in  the  finer  capillaries. 

Sweating. — Shortly  after  the  subsidence  of  the  chill  the  patient 
may  sweat  profusely;  in  arthritic  patients  one  finds  this  most  fre- 
quently; typhoid  and  pneumonic  patients  are  less  apt  to  sweat  after 
the  injections,  but  may  do  so  if  the  injection  is  followed  by  an  in- 
crease in  temperature  and  a  critical  fall. 


THE  NONSPECIFIC  REACTION  53 

A  number  of  observers  have  claimed  that  the  mere  production  of 
a  profuse  perspiration  will  relieve  arthritic  symptoms  and  a  variety 
of  therapeutic  procedures  have  been  elaborated  which  have  as  their 
object  the  production  of  a  sweat,  either  by  applying  external  heat 
or  the  administration  of  a  variety  of  drugs.  There  seems  little  doubt 
that  many  patients  are  relieved  to  some  extent  by  such  measures 
but  there  is  almost  invariably  a  recurrence  of  the  symptoms  after 
the  sweating  has  stopped  for  24  hours.  The  possible  mechanism 
that  is  involved  in  any  therapeutic  stimulation  of  the  skin  such  as 
occurs  when  the  patient  is  sweated  is  discussed  in  the  chapter  on 
the  relation  of  the  skin  to  internal  diseases. 

Nausea  and  Vomiting. — This  is  occasionally  observed  after  rela- 
tively large  doses  of  vaccines  or  after  particularly  toxic  strains  of 
bacteria.  It  is  usually  an  indication  that  the  dosage  has  been  too 
large  or  that  the  patient  is  particularly  sensitive.  The  entire  gastro- 
intestinal tract  will  frequently  show  increased  peristalsis. 

Palpable  Spleen. — Gow  has  observed  that  the  spleen  may  become 
palpable  immediately  after  the  reaction. 

Effect  on  Menstruation. — Lux  has  observed  that  the  menstrual 
flow  is  augmented  after  nonspecific  injections. 

Nervous  Irritability. — Kling  showed  some  years  ago  that  during 
the  period  sensitization  following  on  the  injection  of  some  protein 
parenterally  the  nervous  irritability  of  the  animal  was  considerably 
increased. 

Following  nonspecific  injections  it  has  been  found  that  a  similar 
alteration  tal£es  place  but  the  effect  on  the  threshold  of  the  nerve 
reaction  is  a  diphasic  one.  There  is  for  a  short  period  following 
the  injection  a  lowering  of  the  threshold  for  nerve  stimuli,  clinically 
demonstrable  by  the  increase  in  the  pain,  and  the  general  hyperex- 
citability.  This  is  followed  by  a  period  of  lessened  susceptibility  to 
pain,  somnolence,  and  the  clinical  manifestations  of  the  marked  euphoria 
which  has  been  commented  on  by  almost  every  one  who  has  had 
experience  with  nonspecific  therapy.  Dollken,  working  with  neuritides 
has  observed  a  similar  reaction  in  the  local  effect  on  nerve  tissues. 
He  found  that  after  heterovaccine  injections  there  would  be  a  re- 
sponse on  the  part  of  the  lesion  either  in  a  negative  sense — increased 
pain,  etc.,  or  as  a  positive  phase — analgesia  and  complete  restitution 
to  normal  in  some  instances. 

Herpes  and  Urticaria. — Herpes  has  been  observed  to  follow  a  num- 
ber of  intravenous  injections.  We  have  noted  a  labial  herpes  after  use 
of  typhoid  and  colon  vaccines  (certain  strains  seem  to  be  more  prone 
to  produce  herpes  than  others) .  Auld  has  reported  an  occasional  herpes 
after  intravenous  injection  of  colloidal  metals.  Gow  has  observed  such 
eruptions  after  heterovaccination  and  they  have  also  been  reported 
after  milk  injections. 

Urticarial  eruptions  are  not  so  common.    We  have  observed  one 


54  PROTEIN  THERAPY 

quite  generalized  rash  in  an  arthritic  patient  that  came  on  within 
three  hours  after  the  injection  and  had  disappeared  after  24  hours; 
other  observers  also  report  that  skin  manifestations  are  uncommon 
in  their  experience. 

Headache. — Headache  of  the  frontal  region  is  a  common  symptom 
following  typhoid  and  colon  vaccine  injections,  but  is  observed  less 
frequently  after  milk  and  other  substances.  The  headache  is  not  as  a 
rule  of  long  duration,  lasting  usually  not  more  than  two  or  three  hours 
after  the  chill. 

Delirium. — In  diseases  associated  with  marked  intoxication,  such 
as  typhoid,  typhus  and  erysipelas,  the  intravenous  injection  of  non- 
specific agents  may  at  times  be  followed  by  intensification  of  the 
disease  manifestations  and  among  them  delirium  may  at  times  be  ob- 
served. It  is  usually  a  very  transient  phenomenon  that  disappears  as 
soon  as  the  febrile  reaction  diminishes;  only  rarely  does  one  observe 
any  disorientation  that  persists  past  the  reactive  period  following  the 
injections.  Care  must  of  course  be  observed  in  excluding  alcohol- 
ics from  nonspecific  injections,  for  such  patients  may  develop  a  de- 
lirium tremens  during  the  reaction  which,  once  elicited,  may  lead 
to  a  fatal  termination.  Several  such  cases  have  come  to  our  atten- 
tion. 

Glandular  Activity. — Weichardt  has  carried  out  a  number  of  ex- 
periments in  which  he  has  shown  that  the  injection  of  moderate 
amounts  of  protein  split  products  increase  glandular  activity.  He 
demonstrated  this  in  lactating  goats  as  well  as  for  the  salivary  glands 
of  a  number  of  animals.  Dollken  has  reported  an  increased  secretion 
of  bile  following  milk  injections. 

The  question  of  the  galactagogue  effect  of  parenteral  injections  of 
milk,  of  interest  to  the  pediatrician,  has  been  the  subject  of  con- 
siderable investigation,  but  has  not  been  conclusively  settled. 

Slawik,  during  the  course  of  his  work  with  nonspecific  injections 
in  infants,  had  occasion  to  inject  several  wet-nurses.  Dunkan  is  said 
to  have  observed  a  galactagogue  effect  after  the  injection  of  milk 
parenterally  in  lactating  women,  but  Slawik  in  his  cases  was  not  able 
to  confirm  this  result.  Lonne  has  published  observations  that  indi- 
cate an  increased  secretion  of  milk  after  parenteral  injections,  but 
his  conclusions  have  been  criticized  by  Kirstein,  although  the  latter 
does  not  deny  the  possibility  of  glandular  activation. 

Nitrogen  Metabolism. — The  nitrogen  balance  shows  considerable 
variation  both  experimentally  and  clinically  following  the  parenteral 
introduction  of  the  proteins  and  their  split  products.  It  is  of  course 
beyond  the  scope  of  this  discussion  to  examine  so-called  specific 
dynamic  effect  of  proteins  in  their  general  effect  on  the  normal  metab- 
olism after  ingestion,  although  certain  facts  that  have  been  derived 
from  a  study  of  this  field  indicate  that  there  are  fundamental  differ- 
ences involved  in  the  cellular  reactivity  incident  to  the  digestion  of 


THE  NONSPECIFIC  REACTION  55 

proteins  as  contrasted  to  the  absorption  and  metabolism  of  the  car- 
bohydrates and  fats. 

A  number  of  years  ago  Italian  observers  noted  that  in  normal 
animals  the  injections  of  small  doses  of  toxins  and  of  tuberculin 
were  followed  by  an  augmentation  of  the  nitrogen  metabolism  (ex- 
cretion) followed  by  a  period  in  which  an  excess  of  nitrogen  was 
stored.  Animals  treated  with  small  doses  of  tuberculin  would  gain  in 
weight  as  contrasted  to  normal  animals  without  injections. 

Much  work  has  been  done  during  the  course  of  studies  on  anaphy- 
laxis,  and  inasmuch  as  this  simulates  the  picture  that  we  obtain 
in  nonspecific  therapy  to  a  considerable  degree,  the  results  are  not 
without  interest  in  this  connection.  Schittenhelm  and  Weichardt 
noted  the  immediate  increase  in  the  nitrogen  excretion  in  anaphylactic  v 
dogs  after  a  shock.  Thus  one  dog  from  a  normal  excretion  of  1.88 
gm.  per  day  excreted  2.8,  3.3,  2.65,  2.41  the  days  following  shock, 
amounts  far  in  excess  of  the  amount  of  protein  injected  to  produce 
the  shock.  Segale  noted  the  same  effect  and  Manoiloff  observed  an 
increased  excretion  of  nitrogen  in  rabbits  despite  the  fact  that  the 
temperature  had  diminished. 

Hirsch  and  Leschke  have  studied  the  same  subject  in  a  very 
thorough  manner.  They  found  that  with  fairly  large  doses  of  an- 
aphylatoxin  a  negative  nitrogen  balance  obtained,  whereas  smaller 
doses  or  mild  shocks  often  led  to  a  positive  balance.  They  noticed 
that  the  excretion  of  nitrogen  did  not  necessarily  bear  any  direct 
relation  to  the  temperature  of  the  animal  resulting  from  the  vari- 
ous pyrogenic  agents.  Breed's  studies  are  also  of  interest  in  this 
connection. 

In  the  patient  the  injection  of  the  nonspecific  agents  with  the  re- 
sulting reaction  is  associated  with  an  increase  in  the  nitrogen  ex- 
cretion just  as  such  shocks  are  associated  with  an  increased 
metabolism  in  animals.  In  a  number  of  cases  that  we  have  followed 
the  total  nitrogen  excretion  of  the  urine  increased  from  20%  to  30% 
above  that  excreted  before  the  injection.  After  about  two  days  the 
nitrogen  excretion  again  reaches  the  normal  and  for  a  variable  period 
after  this  time  there  exists  in  many  patients  a  diminution  in  excretion. 

The  Weight  of  the  Patient. — Uddgren  has  followed  the  weight  of  a  J 
series  of  patients  given  intramuscular  milk  injections.  This  included 
4  groups.  In  the  first  were  included  patients  who  received  "market" 
milk,  with  rather  severe  temperature  reactions.  In  the  second  were 
those  who  received  alternating  doses  of  either  "sterile"  or  market  milk. 
In  the  third  group  were  those  who  received  a  series  of  injections  of 
either  the  one  or  the  other.  In  the  fourth  group  were  patients  who 
received  the  "sterile"  milk  entirely.  The  results  were  as  follows: 

I.    Usually  some  increase  of  weight  during  course  of  injections. 
More  often  a  slight  decrease  followed  later  by  an  increase. 


56  PROTEIN  THERAPY 

II.    Well  marked  increase  in  weight. 

III.  Usually  slight  decrease  during  first  series  of  injections,  later 
an  increase. 

IV.  Little  if  any  alteration.    In  a  few  cases  a  well  marked  in- 
crease in  weight. 

In  this  connection  we  must  keep  in  mind  the  possibility  that  such 
changes  in  weight  as  here  observed  may  be  due  to  alterations  in  the 
water  balance  of  the  tissues,  rather  than  an  actual  increase  in  tissue 
substance. 

Albuminuria. — According  to  all  clinical  observers  the  injections  are 
not  followed  by  any  alterations  in  the  urine  that  would  indicate  an  ir- 
ritation of  the  kidney  parenchyma.  The  only  exception  to  this  general 
statement  is  the  effect  that  at  times  follows  the  intravenous  injection 
of  colloidal  metals.  With  these  it  has  been  observed  that  after  the 
subsidence  of  fever  (in  influenza)  the  injection  may  at  times  be  fol- 
lowed by  the  reappearance  of  casts  and  some  albumin  in  the  urine  if 
they  had  been  present  at  the  time  of  the  acute  illness.  In  this  case 
the  agent  seems  able  to  activate  a  low-grade  inflammation  which 
may  still  be  present. 

Uddgren  observed  no  kidney  irritation  in  about  100  cases  in- 
jected with  milk.  In  only  two  cases  was  a  trace  of  albumin  noted 
after  the  injections  and  this  was  a  purely  transient  phenomenon, 
v.  Aaron,  who  examined  the  disposal  of  casein  injected  intravenously 
in  animals,  found  that  58%  of  it  was  excreted  through  the  urine,  a 
fact  that  must  be  considered  if  traces  of  albumin  are  reported  in 
the  urine  after  milk  injections. 

On  the  other  hand,  several  observers  (Dollken,  Schmidt,  etc.) 
have  reported  that  when  nonspecific  injections  are  made  during  the 
course  of  an  acute  illness  accompanied  by  albuminuria  and  casts 
in  the  urine,  the  urinary  findings  clear  up  very  promptly  after  the 
injections.  Dollken  noted  this  particularly  in  his  patients  ill  with 
Weil's  disease  where  a  high-grade  albuminuria  cleared  up  immediately 
after  the  injections. 

Diuresis. —  Injections  are  frequently  followed  by  a  diuresis  of 
some  extent.  Riedel  has  called  attention  to  this  fact. 

Permeability  of  the  Blood  Vessels. — Luithlen  in  1912  studied  the 
effect  of  the  intravenous  injection  of  various  substances,  such  as  serum, 
gelatin,  starch,  and  crystalloids,  on  the  course  of  the  common  skin  re- 
actions and  as  a  result  of  his  preliminary  work  investigated  the  per- 
meability of  the  capillaries  after  such  injections.  His  method  consisted 
in  injecting  Ringer's  solution  into  the  abdominal  cavity  of  rabbits, 
then  following  with  the  intravenous  injection  of  the  agents  that  he 
wished  to  study,  then  determining  the  permeability  of  the  abdominal 
capillaries  by  injecting  sodium  iodid  and  also  sodium  ferrocyanid  in- 
travenously and  testing  the  rate  at  which  these  substances  had  entered 


THE  NONSPECIFIC  REACTION  57 

into  the  fluid  in  the  peritoneal  cavity.  The  colloids  depressed  the  rate ; 
crystalloids  increased  the  permeability  when  studied  under  these  condi- 
tions. Similar  studies  were  made  by  von  den  Velden. 

Siegert  as  well  as  Schmidt  studied  particularly  the  effect  of  pro- 
tein injections  on  the  smaller  vessels.  They  found  that  small  doses 
increased  the  permeability,  while  large  doses  decreased  the  rate.  The 
most  recent  studies  are  those  of  Starkenstein.  These  were  carried 
out  by  producing  corneal  ulcers  in  rabbits  and  then  observing  the 
rate  at  which  dyes  (sodium  fluorescin,  etc.)  would  diffuse  out  at 
the  site  of  the  lesion  after  a  variety  of  nonspecific  injections.  Apart 
from  milk,  albumoses  and  collargol  he  tried  out  a  large  number  of 
drugs  including  quinin,  atophan,  salicylates,  adrenalin,  methylene  blue, 
iodin,  etc.  According  to  his  observation  practically  all  these  sub- 
stances were  followed  by  a  diminution  of  the  permeability  of  the 
capillaries  and  he  accounts  for  their  antiphlogistic  effect  on  this 
basis. 

From  the  effect  noted  on  the  lymph  system  and  the  experiments 
on  the  capillaries  above  described  it  seems  very  probable  that  the 
effect  of  the  nonspecific  injections  is  to  increase  the  permeability 
of  the  capillaries  for  a  short  period  and  later  to  cause  a  definite  lessen- 
ing of  the  permeability.  The  reaction  and  the  direction  of  its  maxi- 
mum effect  will  depend  largely  on  the  dosage  employed  and  to  some 
degree  on  the  agent  used. 

The  Lymphagogue  Effect. — It  is  well  known  that  certain  sub- 
stances, which  Heidenhain  classified  as  lymphagogues  of  the  first  class, 
among  them  peptone,  egg  albumin,  tissue  extracts,  etc.,  cause  a  marked 
increase  in  the  lymph  flow,  supposed  to  be  derived  largely  from  the 
liver  (Starling) .  This  increased  flow  may  continue  a  considerable  time 
following  such  injection.  Teague  and  McWilliams  have  recently  ad- 
vanced the  explanation  that  this  lymphagogue  effect  is  responsible  for 
the  therapeutic  effect  of  protein  injections  in  that  the  antibodies  of  the 
blood  stream  are  forced  into  the  lymph  spaces  and  there  destroy  the  in- 
vading organism.  Davis  and  Petersen  investigated  this  effect  on 
the  lymph  flow,  using  large  dogs  in  whom  a  lymph  fistula  was  estab- 
lished at  the  thoracic  duct  and  then  injecting  killed  colon  vaccine  in- 
travenously to  produce  the  shock  effect.  When  necessary  small  doses 
of  morphin  were  given.  If  the  animals  were  injected  too  soon  after 
the  operation  and  before  complete  recovery  had  been  made  from  the 
anesthetic,  considerable  resistance  to  the  shock  was  manifest  and 
the  temperature  reaction  was  delayed  for  several  hours. 

Lymph  Volume. — The  increase  in  the  rate  of  the  flow  of  the  lymph 
followed  immediately  upon  the  injection  and  in  severe  intoxications 
two  periods  of  maximum  flow  occurred,  the  first  immediately  after 
the  injection  and  persisting  for  from  20  to  30  minutes,  the  second 
after  approximately  1  hour,  the  latter  increase  being  continued  over 
a  longer  period  of  time.  When  the  intoxication  was  not  so  great  the 


58 


PROTEIN  THERAPY 


two-phase  curve  did  not  occur,  the  increase  being  less  in  extent  but 
persisting  for  a  longer  period  of  time.     (Fig.  1.) 

Concentration  of  the  Lymph  and  Serum. — The  concentration  of 
the  lymph  proteins  following  the  injection  is  considerably  increased, 
as  determined  by  the  Kjeldahl  method  for  total  protein  nitrogen, 
while  the  concentration  of  the  nonprotein  nitrogen  may  decrease. 

LYMPH  FLOW 


cc. 

15 
14 
13 
12 
11 

- 

Fn 

1 

10 

9 
6 

7 

- 

U    L 

L 

5 

4 
3 
2 

1 

•— 

-1 

1 

. 

] 

u. 

>— 

; 

i 
> 

i 
1  1  1  1  1  1  ......       ...        ...>.ii> 

5MINUTE  TIME  INTERVALS 

FIG.  1. — Volume  of  lymph  flow  following  Bacillus  coli  vaccine  injection. 

The  Leukocytes. — Few  of  the  changes  following  nonspecific  ther- 
apy have  received  the  study  or  attention  that  the  leukocytic  reaction 
has.  The  earliest  workers  with  nonspecific  methods  of  treatment  fol- 
lowed the  leukocytic  picture  with  great  care,  particularly  because  some 
of  the  earlier  methods — the  fixation  abscess,  yeasts,  nuclein  injections, 
colloidal  metals,  etc. — were  developed  at  a  time  when  clinicians  began 
to  pay  considerable  attention  to  the  leukocytic  count. 

The  role  of  the  leukocyte  in  immune  processes  is  by  no  means 
an  exhausted  field  of  research;  indeed  it  is  one  that  in  many  ways 
seems  to  offer  an  exceptionally  attractive  approach  to  innumerable 
problems  still  obscure.  Nageli  in  his  "Blutkrankheiten"  surmised  that 
a  leukocytosis  that  resulted  as  an  expression  of  an  immune  reaction 
on  the  part  of  the  bone  marrow  might  be  of  decided  therapeutic  use. 
Fiessinger  and  Marie  have  for  many  years  emphasized  the  impor- 
tance of  the  enzymes  of  the  leukocytes  in  infectious  disease  while 
the  work  of  Metchnikoff  and  his  pupils  has  so  thoroughly  covered 
the  general  field  of  phagocytosis  that  it  will  be  unnecessary  to  enter 


THE  NONSPECIFIC  REACTION  59 

into  a  subject  that  is  so  well  known  and  the  literature  of  which  is 
so  accessible.  The  discussions  in  Zinsser's  "Infection  and  Resistance" 
give  a  comprehensive  idea  of  the  subject. 

The  experimental  production  of  a  leukocytosis,  and  the  study  of 
the  leukocytosis  that  is  produced  after  the  injection  of  a  variety  of 
substances  of  bacterial,  protein  or  chemical  derivation  have  been  car- 
ried on  for  a  considerable  period  and  inasmuch  as  the  results  are 
quite  comparable  with  those  obtained  in  the  human  it  may  be  well 
for  a  moment  to  consider  the  present  status  of  our  knowledge  of  the 
subject. 

The  effect  of  the  injection  of  bacteria  and  bacterial  extracts  on  the 
leukocytes  was  studied  experimentally  by  a  large  number  of  investigators. 
Lange,  injecting  typhoid  bacilli  in  rabbits,  noted  that  after  large  doses 
there  was  an  immediate  leukopenia  that  was  later  followed  by  a  recovery 
and  a  leukocytosis,  in  one  of  his  cases  going  to  43,900.  Polymorphonuclears 
were  found  to  predominate,  with  transitional  and  large  mononuclear  cells 
appearing  later.  He  observed  the  presence  of  normoblasts  as  well  as 
a  polychromatophilia ;  myelocytes  were  also  noted.  Goldscheider  and 
Jacob  using  staphylococci  observed  a  similar  reaction,  although  the  re- 
active leukocytosis  did  not  reach  the  extreme  degree  that  Lange  found. 
Schlesinger  using  streptococci  could  only  determine  a  leukopenia.  When 
typhoid  bacilli  were  used  for  a  repeated  series  of  injections  Hirschfeld 
found  that  the  bone  marrow  became  atrophic.  Studer  studied  the  effect 
of  typhoid  and  coli  toxin  on  the  leukocytes  and  Friedlander  using  staphylo- 
cocci observed  that  with  these  organisms  he  obtained  a  maximum  leu- 
kocytosis with  relatively  no  leukopenia  preceding  it.  Samson-Himmel- 
stjerna,  one  of  the  earlier  observers,  noted  a  leukopenia  after  peptone  in- 
jections. 

Andrews  found  that  the  colon  bacillus  produced  the  greatest  leu- 
kopenia in  rabbits,  staphylococci  and  diphtheroid  bacilli  less  than  colon 
bacilli.  He  was  of  the  opinion  that  in  immunized  animals  there  was  a 
more  pronounced  reactive  leukocytosis  than  in  normal  animals. 

Gay  and  Claypole  in  their  work  on  the  mechanism  of  recovery  in 
typhoid  fever  reported  studies  which  seemed  to  support  the  contention  that 
in  immunized  animals  the  leukocytic  response  on  reinjection  was  greater 
than  in  normal  animals  and  that  this  was  a  specific  reaction.  McWilliams 
was  not  able  to  confirm  these  findings.  It  is  very  probable  that  as  a  re- 
sult of  sensitization  the  whole  organism  becomes  more  responsive  and 
will  react  more  readily  and  more  intensely  to  a  reinjection,  but  recent 
work  such  as  that  of  Bieling  would  rather  indicate  that  to  a  considerable 
degree  it  is  immaterial  what  the  agent  is  which  is  injected,  as  long  as  it 
has  an  irritant  or  stimulating  effect. 

Schittenhelm,  Weichardt  and  Greisshammer  went  over  this  phase  of 
the  reaction  of  animals  to  bacterial  and  other  proteins  and  came  to  the 
following  conclusions : 

The  intravenous  injection  of  native  protein,  peptone  and  bacterial  pro- 
tein causes  in  the  dog  an  immediate  leukopenia  depending  not  only  on 
the  size  of  the  dose  but  on  the  character  of  the  agent.  Native  protein  pro- 


60  PROTEIN  THERAPY 

duces  such  a  leukopenia  only  after  sensitization,  peptone  with  the  first 
injection.  Among  the  bacterial  agents  the  typhoid  bacillus  when  injected 
produces  the  most  persistent  leukopenia ;  some  varieties  of  tuberculin,  colon 
bacilli  and  staphylococci  also  have  the  same  effect.  On  reinjection  the 
leukopenia  becomes  less  marked  in  degree  and  duration.  The  authors  sug- 
gest that  this  effect  is  due  to  a  functional  paralysis  or  depression  of  the 
bone  marrow.  It  is  probable  that  in  a  great  part  the  peripheral  leukopenia 
so  observed  is  due  to  the  accumulation  of  the  leukocytes  in  the  internal 
organs — spleen,  liver,  etc.  If  the  injected  dose  is  too  large  the  animal 
of  course  dies  in  this  shock  or  depression  stage. 

The  stage  of  leukopenia  is  followed  by  one  of  leukocytosis  which  per- 
sists for  from  three  to  six  days ;  the  degree  of  the  reaction  is  diminished  on 
further  injections.  Of  the  bacterial  injections  typhoid  and  staphylococci 
produce  the  most  marked  leukocytosis. 

This  reactive  leukocytosis  that  follows  is  of  myeloid  type — that  is,  of 
neutrophile  polymorphonuclears,  large  mononuclears  and  transitional  types. 
Eosinophils  are  at  times  also  increased.  The  lymphatic  apparatus  is  rela- 
tively passive. 

The  protein  split  products  and  the  bacterial  proteins  also  stimulate  the 
hematopoietic  system,  as  indicated  by  the  appearance  of  normoblasts,  meg- 
aloblasts  and  polychromatic  reds  in  the  days  following  the  injection. 

Two  or  more  factors  enter  into  these  changes  that  have  been  observed 
in  the  relation  of  the  leukocytes  after  nonspecific  injections.  The  leuko- 
penia that  follows  immediately  is  due  to  an  accumulation  of  the  leukocytes 
in  the  internal  organs — lungs,  spleen,  liver,  gastrointestinal  tract  and  the 
bone  marrow.  Dale  is  inclined  to  the  belief  that  because  of  changes  in 
the  intima  of  the  capillaries  and  smaller  vessels  the  leukocytes  tend  to 
adhere  to  the  walls  and  therefore  do  not  appear  in  the  circulating  blood. 
The  leukocytosis  that  follows  the  leukopenia  is  a  reactive  phenomenon  due 
to  a  stimulation  of  the  bone  marrow.  Andrews  followed  the  Arneth  count 
and  found  that  the  neutrophils  with  undivided  nuclei  outnumbered  the 
divided  ones.  The  presence  of  bone  marrow  cells  of  various  types  after  the 
reaction  was  further  evidence  of  the  stimulation  of  the  marrow. 

During  the  height  of  the  reaction  the  leukocytes  are  more  actively 
phagocytic  than  normally,  the  ingestion  of  erythrocytes  by  the  polymorpho- 
nuclear  leukocytes  being  observed  after  typhoid  injection. 

That  a  leukocytosis  followed  the  subcutaneous  injection  of  nu- 
cleins  was  noted  when  they  were  introduced  about  thirty  years  ago; 
Bauer  studied  the  leukocytosis  that  followed  the  fixation  abscess 
and  a  similar  reaction  on  the  part  of  the  leukocytes  was  observed  to 
some  degree  after  serum  injections,  after  the  intravenous  injection 
of  colloidal  metals,  following  autoserotherapy,  etc. 

With  the  development  of  nonspecific  therapy  and  the  endeavor 
to  find  a  satisfactory  theoretical  basis  for  the  therapeutic  results 
obtained,  a  number  of  investigators  naturally  turned  to  the  study 
of  the  leukocytic  reaction  and  its  possible  bearing  on  the  problem. 
Some  believe  that  the  chief  factor  in  the  therapeutic  result  lies  in 
the  leukocytic  stimulation,  others  see  merely  an  accessory  factor  in 


THE  NONSPECIFIC  REACTION  61 

the  leukocytic  response,  still  others  deny  the  leukocyte  any  role  in 
the  mechanism  of  recovery  by  nonspecific  methods.  The  problem  is 
one  of  considerable  importance  and  it  may  be  well  to  consider  the 
facts  that  have  been  reported. 

Scully  studied  the  leukocytosis  in  some  detail.  In  his  arthritic 
cases  treated  with  typhoid  vaccine  injected  intravenously,  the  injec- 
tion was  first  followed  by  a  leukopenia  (the  leukocytes  dropping  from 
an  average  of  14,000  to  about  5,000),  following  this  the  process  would 
be  reversed  and  a  leukocytosis  make  its  appearance.  This  would 
frequently  reach  30,000  or  40,000;  in  one  case  the  count  was  62,000. 
When  subsequent  injections  were  made  the  reaction  was  usually  less 
marked. 

In  the  primary  leukopenia  Scully  found  that  the  absolute  number 
of  polymorphonuclear  leukocytes  decreased,  rising  later  from  the  nor- 
mal of  about  60%  to  over  90%  of  the  total.  Scully  found  that  the 
large  mononuclears  were  decreased  during  the  first  three  hours,  but 
after  that  again  maintained  their  normal  proportion.  The  lym- 
phocytes were  relatively  and  absolutely  decreased,  as  were  the  eosino- 
philes,  although  these  latter  at  times  showed  a  slight  increase  later. 

Rohonyi  found  that  the  leukocytes  increased  following  typhoid  vac- 
cine injections  but  that  the  leukocytosis  bore  no  relation  to  the  thera- 
peutic effect  obtained.  He  also  noted  that  there  was  some  increase 
in  eosinophiles.  Gow  also  studied  the  blood  cytology  in  the  cases 
that  he  treated  with  heterovaccines  and  peptone  injections.  He  ob- 
served the  primary  leukopenia  which  involved  all  elements  and  noted 
that  after  one  hour  the  polymorphonuclear  leukocytes  still  outnum- 
bered the  lymphocytes  but  that  from  that  time  on  the  young  forms 
of  neutrophils  became  more  abundant  (the  neutrophils  with  un- 
divided nuclei  outnumbered  those  with  divided  nuclei).  After  72 
hours  he  was  of  the  impression  that  preinjection  conditions  were  re- 
stored. During  the  height  of  the  leukocytic  reaction  his  counts 
averaged  from  20,000  to  30,000  and  myelocytes  and  normoblasts  were 
to  be  observed. 

Holler  and  Weiss  studied  the  leukocytosis  that  was  to  be  ob- 
served after  milk  injections,  as  did  also  Schmidt  and  Kaznelson.  The 
latter  observers  found  a  very  slight  increase  in  the  eosinophiles  after 
the  first  stages  of  the  reaction  had  subsided.  Their  observations  on 
the  lymphocytes  would  lead  one  to  believe  that  the  effect  on  these 
blood  elements  was  more  protracted  than  Gow's  observations  would 
indicate.  They  state  that  they  were  increased  over  the  normal  for 
a  period  of  several  days  after  the  polymorphonuclear  leukocytes 
had  reached  preinjection  figures. 

Schmidt  and  Kaznelson  have  grouped  the  leukocytic  reaction  that 
follows  parenteral  milk  injection  into  three  classes.  They  observed 
first  a  group  in  which  a  primary  leukopenia  was  followed  by  a  leu- 
kocytosis consisting  largely  of  polymorphonuclear  neutrophils.  In 


62  PROTEIN  THERAPY 

a  second  group,  in  which  a  leukocytosis  was  already  present  (as  in 
leukemias)  the  injection  was  followed  by  a  decrease  in  the  number 
of  neutrophiles.  In  the  third  group  the  reaction  consisted  chiefly 
in  an  increase  in  the  number  of  mononuclear  elements. 

Miiller  has  emphasized  particularly  the  myelocytic  stimulation  that 
is  brought  about  by  milk  injections.  While  the  lymphatic  apparatus 
was  practically  unaffected,  myelocytes  were  thrown  into  the  circula- 
tion in  abundance,  indicating  a  marked  stimulation  of  the  bone  mar- 
row. 

Recently  Nagao  has  studied  the  cellular  changes  that  follow  the 
intravenous  injection  of  killed  nonhemolytic  streptococci  into  guinea- 
pigs.  Most  of  the  cocci  were  taken  up  in  leukocytes  within  five 
or  ten  minutes,  and  cocci  could  be  found  in  circulating  leukocytes 
for  as  long  as  three  hours.  The  cocci  and  polymorphonuclear  leu- 
kocytes accumulate  in  the  lungs  during  the  first  ten  minutes,  and  it 
is  here  that  most  of  the  cocci  reach  the  interior  of  the  phagocytes.  At 
the  same  time  there  is  a  general  leukopenia,  and  the  polymorphonuclear 
leukocytes  of  the  spleen  are  reduced  to  about  one-fourth  the  nor- 
mal number.  There  is  a  similar  reduction  of  such  leukocytes  in  the 
bone  marrow.  After  thirty  minutes  the  lungs  are  nearly  normal, 
the  number  of  leukocytes  in  the  blood  may  be  normal  or  increased, 
and  there  is  a  beginning  accumulation  of  the  leukocytes  in  the  liver 
and  spleen.  There  is  also  a  marked  proliferation  of  the  endothelial 
cells  of  the  liver  and  spleen,  and  of  the  leukocytes  of  the  bone  mar- 
row. In  from  two  to  three  hours  there  is  a  marked  accumulation  of 
leukocytes  with  ingested  cocci  in  the  liver  and  spleen,  the  number 
of  leukocytes  in  the  blood  is  increased,  and  immature  leukocytes  ap- 
pear in  the  blood  and  bone  marrow,  indicating  an  exhaustion  of  the 
leukocyte- forming  power  of  the  marrow.  It  is  suggested  by  Nagao 
that  the  reaction  of  a  patient  to  vaccine  treatment  may  be  deter- 
mined in  some  degree  by  frequent  examination  of  the  blood,  the  ap- 
pearance in  it  of  immature  leukocytes  indicating  danger  of  exhaustion 
of  leukocytogenic  centers  in  the  marrow  and  elsewhere. 

Cowie  and  Calhoun  in  this  country  made  a  detailed  study  of  the 
leukocytic  reaction  following  intravenous  typhoid  injections.  They 
observed  the  primary  leukopenia  and  found  that  the  maximum  re- 
action took  place  between  the  4th  and  the  9th  hour  after  the  in- 
jection, their  leukocyte  counts  then  ranging  about  30,000.  The  poly- 
morphonuclear cells  which  appeared  were  new  cells  with  large  nuclei. 
Large  lymphocytes  frequently  disappeared  at  some  time  following  the 
injection.  The  small  lymphocytes  never  wholly  disappeared  although 
they  were  greatly  decreased,  in  one  case  to  200  cells  per  c.mm.  The 
transitional  cells  were  usually  below  normal  in  number  while  the 
eosinophiles  were  not  increased.  They  observed  the  appearance  of 
great  numbers  of  myelocytes  which  were  to  be  found  sometimes  within 


THE  NONSPECIFIC  REACTION  63 

one-half  hour  after  the  injection  and  in  one  case  reached  the  total 
of  800  cells  per  c.mm.  Among  these  basophiles  were  frequently  ob- 
served. Nucleated  red  cells,  both  megaloblasts  and  normoblasts,  were 
also  observed.  Tiirck  irritation  forms  were  also  noted  (acidophile 
granular  lymphocyte  forms)  and  irregular  small  lymphocytes.  Cowie 
and  Calhoun  consider  that  the  leukopenia  is  due  to  an  emigration 
of  the  leukocytes  to  the  internal  organs.  According  to  their  observa- 
tion they  obtained  the  most  satisfactory  clinical  results  in  those 
patients  that  responded  best  with  a  high  leukocytosis. 

Holler,  on  the  other  hand,  does  not  consider  a  leukocytosis  an 
essential  factor  in  the  therapeutic  result.  Liidke  as  well  as  Holler 
noted  a  slight  eosinophilia  after  the  albumose  injections. 

Other  nonspecific  agents  produce  a  leukocytosis  of  varying  degree 
and  studies  have  been  made  on  the  blood  cytology  following  in- 
jections of  serum,  nucleins,  colloidal  metals,  salt  solution,  turpentine, 
iodids  and  a  number  of  related  substances.  (Pfenninger;  Hammett, 
Kessler  and  Browning;  Paaschen;  Fiessinger  and  Marie,  etc.) 

Miiller  considers  that  digestion  leukocytosis  represents  merely 
the  leukocytic  reaction  to  the  protein  split  products  absorbed  dur- 
ing the  course  of  digestion. 

The  Erythrocytes. — Schittenhelm,  Weichardt  and  Griessheimer  ob- 
served the  erythropoietic  irritation  that  followed  a  variety  of  bacterial 
injections,  just  as  other  observers  before  them  had  noted  the  presence 
of  many  nucleated  red  cells  after  such  intravenous  injections.  Clinic- 
ally it  has  been  observed  that  the  red  count  is  increased  after  non- 
specific injections  in  anemia;  in  pernicious  anemia  the  increase  is  as  a 
rule  transient  and  uncertain. 

Platelets. — Duke  has  observed  that  small  doses  of  typhoid  vaccine 
increase  the  number  of  blood  platelets  while  larger  doses  cause  a 
diminution  in  the  number.  Cowie  and  Calhoun  report  that  the  platelets 
after  typhoid  injection  increase  in  number  and  size.  Dollken,  on  the 
other  hand,  found  no  constant  alteration  in  the  platelets  after  milk  in- 
jections although  he  found  a  decided  styptic  effect  from  such  injections 
in  cases  of  hemorrhagic  diathesis.  He  concluded  from  his  observa- 
tions that  the  platelets  were  probably  not  concerned  in  the  altera- 
tion in  the  coagulation  rate. 

Blood  Sugar. — Lowy  observed  a  very  prompt  increase  in  the 
amount  of  blood  sugar  following  nonspecific  injections.  (Milk.) 

Fibrinogen. — The  amount  of  fibrinogen  in  the  blood  is  increased  in 
about  6  hours  after  milk  injection  and  remains  at  a  high  level 
for  a  period  of  about  8  days.  (Lowy,  von  der  Velden.)  Moll  ob- 
served the  increase  in  fibrinogen  after  the  injection  of  gelatin  and 
serum. 

Thrombokinase. — Thrombokinase  is  increased  very  shortly  after 
milk  injections.  Deutero-albumoses,  bacteria  and  colloidal  metals 
have  little  effect  on  the  coagulation  mechanism. 


64  PROTEIN  THERAPY 

Serum  and  Lymph  Enzymes. — During  the  course  of  a  series  of 
studies  on  the  alterations  in  serum  enzymes  in  animals  after  anaphy- 
lactic  shock,  after  the  intravenous  injection  of  protein  split  products, 
of  bacteria,  of  kaolin,  of  trypsin,  etc.,  Jobling  and  his  associates  estab- 
lished the  fact  that  as  a  result  of  these  various  injections  the  animal 
responded  with  a  mobilization  of  proteolytic  enzymes  as  well  as  of 
lipases.  Diastase  was  not  altered  to  the  extent  that  the  other  enzymes 
were  changed.  The  increase  in  the  titer  of  the  protease  was  very  strik- 
ing after  severe  intoxications  such  as  those  produced  by  typhoid  or 
colon  bacilli. 

In  view  of  the  fact  that  the  flow  of  the  lymph  is  markedly  augmented 
and  dilutes  the  blood  and  that  the  blood  volume  is  greatly  diminished  after 
shock  because  of  the  increased  permeability  of  the  vessels  (Dale  has  re- 
cently observed  a  diminution  of  the  volume  by  as  much  as  40%  after  his- 
tamin  injection),  Davis  and  Petersen  studied  the  enzymes  of  the  blood 
and  lymph  separately  after  intravenous  injection  of  colon  vaccine.  The 
results  of  these  experiments  were  as  follows: 

Protease. — The  effect  of  the  bacterial  shock  on  the  protease  content  of 
the  lymph  and  serum  was  marked  in  extent.  Three  types  of  reaction  could 
be  distinguished:  (a)  the  fluctuations  in  titer  may  occur  simultaneously, 
(b)  those  of  serum  may  precede  those  of  the  lymph,  and  finally  (c)  there 
may  be  no  relation  of  the  one  to  the  other. 

Peptidase. — The  fluctuations  of  the  peptidase,  or  ereptase  titer,  do  not 
parallel  those  of  the  protease;  indeed  the  curves  may  be  quite  dissimilar. 
As  a  rule  the  increase  makes  its  appearance  later  than  that  of  the  protease 
and  is  less  extensive.  When  alterations  in  titer  do  occur  they  appear 
almost  simultaneously  in  both  the  lymph  and  serum,  although  in  a  few 
experiments  the  ferment  was  first  to  be  observed  in  the  serum.  It  is  at 
any  rate  apparent  that  the  entrance  into  the  blood  stream  can  be  direct 
and  does  not  need  to  take  place  via  the  lymph  channels,  although  under 
normal  conditions,  i.e.,  feeding,  this  seems  to  be  the  one  portal  of  entry. 

Lipase. — While  the  increase  in  this  ferment  occurs  in  both  lymph  and 
blood  following  shock,  it  seems  to  make  its  appearance  first  in  the  serum. 

In  the  patient  the  effects  of  nonspecific  injections  on  the  enzymes 
are  not  as  marked  as  they  are  in  experimental  animals.  In  a  study 
of  serum  alterations  in  patients  after  nonspecific  therapy,  Petersen 
followed  the  changes  to  be  observed  in  (a)  the  stalagmometric  read- 
ings, in  (b)  the  total  nitrogen  of  the  serum  (concentration  of  the 
serum),  (c)  the  noncoagulable  nitrogen,  and  the  titer  of  the  enzymes, 
(d)  protease,  (e)  ereptase,  (f)  diastase  and  (g)  esterase. 

The  results  were  as  follows: 

(a)  There  was  a  concentration  of  the  serum. 

(b)  The  nonprotein  nitrogen  was  practically  unaltered. 

(c)  The  serum  protease  almost  invariably  decreased  after  the  shock 
but  later  increased  progressively  for  a  period  of  from  three  to  four  days. 


THE  NONSPECIFIC  REACTION 


65 


(d)  The  serum  peptidase  usually  increased  in  the  cases  that  responded 
with  clinical  improvement. 

(e)  The  diastatic  activity  of  the  serum  usually  diminished. 

(f)  The  lipolytic  activity  of  the  serum  showed  no  constant  alteration. 


Per 

:i?n 
60 

bo 


Zo 


60 
bo 
4o 
Zo 


60 


Zo 


B 


Fia.  2.— Changes  in  antiferment  titer  following  protein  shock.    X  indicates 
injection. 


66  PROTEIN  THERAPY 

The  Antiferment. — In  the  course  of  studies  undertaken  several 
years  ago  Jobling  and  Petersen  presented  evidence  that  seemed  to 
indicate  very  strongly  that  the  anti-enzyme  (antitrypsin)  of  the  serum 
consisted  of  the  finely  dispersed  lipoids  which  contained  unsaturated 
carbon  bonds  in  their  chemical  structure.  More  recent  research  has  in 
general  confirmed  the  view  that  the  antienzyme  is  lipotropic  and  not 
related  to  the  proteins  although  it  may  physically  be  closely  bound  to 
some  of  these  serum  constituents. 

In  animal  experimentation  Jobling  and  Petersen  determined  that 
there  was  an  increase  in  the  antiferment  after  practically  every 
form  of  shock  to  which  the  animal  was  subjected — anaphy lactic,  bac- 
terial, protein,  etc.  Clinically  it  had  been  observed  that  the  anti- 
ferment  was  increased  in  cachexia,  during  acute  febrile  diseases,  j.n 
pregnancy,  after  vaccine  injection,  serum  sickness,  etc. 

In  the  patient  injected  with  vaccines  intravenously  the  fluctua- 
tion in  the  antiferment  titer  were  followed  by  Petersen  and  the  types 
of  reaction  are  illustrated  in  the  accompanying  chart  (Fig.  2). 

"The  changes  in  the  antiferment  of  the  blood  serum  are  usually  well 
marked  and  quite  uniform  in  the  cases  that  react  favorably  to  the  shock 
therapy.  Chart  A  illustrates  the  changes  taking  place  for  a  three-day 
period  of  observation  in  a  case  with  complete  recovery  from  an  acute 
arthritis  following  intravenous  injection  of  60  mg.  of  a  primary  proteosa 
The  persistence  of  the  increased  antiferment  titer  may  be  much  less  in 
duration,  as  shown  in  the  Chart  B.  This  case,  K.  H.,  was  one  of  multiple 
subacute  arthritis  which  did  not  improve  to  any  marked  extent  after  in- 
jection of  typhoid  vaccines,  although  there  was  temporary  relief. 

"Finally,  the  cases  that  show  no  permanent  improvement  seldom  show 
any  increase  in  the  antiferment,  indeed  almost  always  present  a  decrease 
in  the  titer  following  the  shock,  as  illustrated  in  the  third  and  fourth 
charts,  C  and  D." 

Antibodies. — With  the  introduction  of  modern  methods  of  nonspe- 
cific therapy  immunologists  turned  naturally  to  an  investigation 
whether  or  not  the  therapeutic  effect  of  the  injections  might  not  be 
due  to  some  alteration  in  the  antibody  titer  of  the  serum  of  the  patient. 
As  a  matter  of  fact  the  effort  to  increase  antibody  production  by  stimu- 
lating the  organism  in  a  variety  of  ways  is  by  no  means  a  recent 
subject  of  experimentation.  Thus  Solomonsen  and  Madsen  found 
that  if  horses  were  immunized  with  diphtheria  toxin  and  then  in- 
jected with  pilocarpin  the  titer  was  much  higher  than  before  the 
pilocarpin  injections.  Obermeier  and  Pick,  using  5%  and  10%  pep- 
tone solution  for  injection,  found  that  animals  sensitized  three  months 
previously  responded  with  a  marked  increase  in  precipitins  after  the 
injections.  Dieudonne  immunized  rabbits  with  typhoid  bacilli  and 
then  injected  hetol  and  observed  a  decided  increase  in  the  antibody 
titer.  Similar  observations  have  been  recorded  for  nucleins,  for 
colloidal  metals  and  for  paraspecific  serum  injections. 


THE  NONSPECIFIC  REACTION  67 

Hektoen,  working  with  rabbits  sensitized  long  before  to  horse 
serum,  found  that  when  at  a  subsequent  period  the  same  animals  were 
injected  with  some  other  variety  of  serum,  the  animals  again  yielded 
the  specific  horse  agglutinin  first  formed.  This  flushing  out  of  a 
specific  antibody  under  the  stimulus  of  some  other  and  quite  differ- 
ent protein  has  been  suggested  as  a  basis  of  the  therapeutic  effect 
of  nonspecific  therapy. 

Thus  Miiller  and  Weiss  thought  that  this  was  the  explanation  of 
their  results  in  the  treatment  of  gonorrheal  complications  with  gon- 
ococcus  and  other  vaccine,  but  serological  tests  failed  to  confirm  this 
view.  Ichikawa  assumed  the  same  basis  for  his  experiments  in 
typhoid. 

Experimentally  the  results  of  Conradi  and  Bieling,  and  Bieling 
deserve  much  interest  in  this  connection,  indeed  the  facts  brought 
out  in  Bieling's  recent  paper  would  seem  to  have  a  direct  bearing  oni 
a  number  of  important  questions  in  infectious  diseases.  Conradi 
and  Bieling  treated  rabbits  with  typhoid  bacilli  and  determined  the 
titer  of  agglutinin.  They  then  injected  colon,  dysentery  and  diph- 
theria bacilli  and  observed  the  same  increase  in  agglutinins  that 
has  been  described  in  Hektoen's  paper.  Bieling  has  continued  these 
experiments  and  has  found  that  animals  sensitized  to  dysentery  are' 
able  to  form  antibodies  against  typhoid  bacilli  when  only  minute 
doses  of  typhoid  antigen  are  injected  into  them.  The  sensitized  ani- 
mals can  elaborate  specific  antibodies  when  only  a  minute  fraction 
of  the  amount  of  the  new  antigen  that  would  be  required  in  a  normal 
animal  is  injected.  In  other  words,  the  first  immunization  leaves  the 
animal  in  a  state  of  nonspecific  hypersensitiveness  during  which  it  is 
much  more  reactive  to  stimuli  of  all  kinds. 

The  results  of  these  experiments  which  have  been  confirmed  and 
extended  by  Pinner  and  Ivanfievic  have  their  direct  bearing  on  the 
problem  under  consideration  and  aid  in  explaining  some  of  the  di- 
vergent observations  tfrat  have  been  recorded  by  clinicians  after  non- 
specific injections.  We  may  expect  that  if  injections  are  made  in 
patients  who  have  been  previously  immunized  that  they  will  respond 
with  an  increase  in  the  antibody  titer  of  the  serum;  if  they  are  in- 
jected during  the  course  of  a  disease,  antibodies  which  have  been 
formed  in  the  cells  but  not  yet  cast  off  may  be  "shed"  as  Larson  has 
suggested,  and  we  may  then  determine  an  increase  in  the  serum.  On 
the  other  hand,  if  they  have  been  thrown  into  the  circulation  during 
the  course  of  a  disease  as  rapidly  as  formed,  we  cannot  expect  any 
increase  in  the  titer.  We  may  also  assume  that  with  the  stimulation 
of  the  cellular  activity  ("plasmaactivation")  the  cells  will  respond 
by  producing  an  increased  amount  of  antibodies  if  they  are  still 
capable  of  such  response. 

Baluit  found  that  in  typhoid  patients  injected  intravenously  with 
typhoid  vaccine,  there  was  no  definite  alteration  in  the  antibodies 


68  PROTEIN  THERAPY 

unless  perhaps  an  increase  in  the  opsonins.  The  agglutinins  and 
bactericidal  substances  were  not  increased. 

Liidke  found  the  complement  somewhat  decreased  but  found  that 
there  was  no  consistent  increase  in  antibodies,  v.  Groer  as  well  as 
Svestka  and  Marek  observed  no  increase  in  agglutinins  after  the 
injection  of  "typhin"  in  typhoid  patients.  Dollken,  using  milk,  noted 
that  the  injections  did  not  alter  the  titer  of  dysentery  agglutinins  in 
patients  ill  from  dysentery.  When  he  used  a  specific  vaccine  he  did 
observe  an  increase  of  these  antibodies,  but  clinically  there  was  no 
difference  in  the  effect  on  the  disease  whether  milk  or  specific  vaccine 
was  used.  Reibmayr  also  found  no  changes  in  the  agglutinins  follow- 
ing the  injection  of  typhoid  vaccines. 

Flechseder,  on  the  other  hand,  observed  an  increase  in  agglutinins 
after  albumose  injections  in  typhoid  patients,  while  Parlavecchio  found 
an  increase  in  agglutinins  and  in  complement  after  the  injection  of 
nucleins.  Borchardt  determined  that  organ  extracts  (adrenalin, 
spermin,  thyroid,  etc.)  increased  the  agglutinin  titer  of  experimental 
animals,  in  one  case  from  a  titer  of  1:20  to  1:5120  and  in  another 
case  from  1:1280  to  1:12,240. 

Culver's  investigations  are  perhaps  the  most  extensive  in  this 
field.  The  opsonins  and  bactericidal  substances  were  studied  in  the 
serum  of  sixteen  patients  suffering  from  gonorrheal  arthritis.  An 
injection  of  killed  gonococci  or  proteose  solution  was  given  intra- 
venously every  seventy-two  to  ninety-six  hours  until  three  to  five  in- 
jections had  been  given.  The  serum  was  taken  for  study  just  before 
each  injection.  Ten  of  these  patients  received  successive  injections  of 
proteose  and  six  received  killed  gonococci.  No  marked  difference  was 
seen  in  the  results  of  the  two  groups. 

His  conclusions  are  as  follows:  "Primary  and  secondary  proteose 
preparations  stimulate  antibody  production  or  mobilization  for  spe- 
cific organisms  in  gonococcal  arthritis,  in  a  manner  not  to  be  dis- 
tinguished from  that  produced  by  the  injection  of  the  specific  organisms 
themselves. 

"In  gonococcal  arthritis,  there  is  either  no  change  or  a  decrease 
in  the  antibody  content  of  serum  within  the  first  twenty-four  hours 
following  an  intravenous  injection,  in  all  excepting  the  first  injection 
when  the  lytic  substances  seem  to  be  slightly  increased  during  this 
time. 

"In  favorable  cases  the  first  injection  usually  causes  the  greatest 
clinical  benefit.  However,  refractory  patients  may  give  a  similar 
lysin  increase  during  the  first  twenty-four  hours  following  an  injec- 
tion; hence  the  subjective  and  objective  improvement  in  favorable 
cases  cannot  be  unquestionably  attributed  to  an  increase  in  anti- 
bodies alone.  However,  little  as  these  substances  may  have  to  do 
with  the  early  relief  of  symptoms  in  gonococcal  arthritis,  it  may  be 


NONSPECIFIC  REACTION  69 

that  they  have  considerable  to  do  with  the  final  recovery  from  the 
infection  by  their  influence  upon  the  primary  focus." 

Culver  observed  that  both  the  opsonic  and  bacteriolytic  titers  of 
the  serum  of  patients  suffering  from  gonococcal  arthritis  were 
normal  or  below  normal  before  any  injections  were  made.  This 
has  been  previously  observed  by  Irons  and  others  for  the  opsonin 
content  of  serum  from  these  patients.  Irons  also  demonstrated  that 
spontaneous  fluctuations  in  antibody  content  occur  in  gonococcal 
arthritis  and  that  by  massage  of  the  affected  joints  or  the  infected 
prostate  there  resulted  an  opsonin  increase  not  altogether  unlike 
that  produced  by  an  injection  of  killed  gonococci.  Culver  believes 
that  any  antibody  change  which  results  from  an  injection  of  a  sub- 
stance which  produces  a  chill  might  well  be  explained  by  the  motion 
of  the  affected  parts  during  the  chill.  But  since  the  curves  regularly 
show  an  increase  in  lysin  and  a  decrease  in  opsonin  after  the  first 
injection  and  reaction,  while  each  succeeding  injection  is  usually  fol- 
lowed directly  by  an  antibody  decrease  regardless  of  the  intensity  of 
the  reaction,  it  does  not  seem  that  the  joint  motion  has  much  to 
do  with  it  here.  The  above  antibody  changes  occur  in  serum  of 
patients  with  acute,  subacute,  or  chronic  joints  with  no  appreciable 
difference  between  these  classifications.  Some  serums  were  studied 
after  a  small  amount  of  protein  was  injected,  large  enough  to  increase 
the  leukocytes  and  temperature  but  not  sufficient  to  produce  a  rigor. 
These  injections  were  followed  by  antibody  changes  not  unlike  those 
produced  by  the  more  severe  reactions. 

The  Effect  on  the  Wassermann  Reaction.— Uddgren  found  that 
following  milk  injections,  Wassermann  negative  luetic  patients  fre- 
quently became  Wassermann  positive.  Zeisl  finds  that  gonorrhea! 
patients  after  an  injection  of  "Gonargin"  or  "Arthigon"  may  give  a 
positive  reaction.  This  observation  is  related  to  that  of  Strickler, 
Munson  and  Sidlick  who  found  that  after  salvarsan  injections  non- 
syphilitic  patients  may  become  serologically  positive.  Conradi  and 
Sklarek  have  also  observed  changes  in  the  Wassermann  reaction  after 
intravenous  injections  of  typhoid  vaccine. 


CHAPTER  IV 
THE   FOCAL  REACTION 

In  the  preceding  chapter  the  changes  that  take  place  in  the 
organism  after  nonspecific  injections  have  been  discussed  in  detail. 
We  will  now  have  to  consider  a  related  subject  of  utmost  importance 
from  the  therapeutic  as  well  as  the  theoretical  standpoint,  namely,  the 
focal  reaction  that  becomes  evident  about  inflammatory  foci  after 
nonspecific  injections.  Just  as  the  general  symptomatology  of  the 
patient  may  be  accentuated  after  the  injections,  so  it  has  been  ob- 
served that  preexisting  inflammatory  lesions,  endogenous  or  exogenous 
in  origin,  will  very  frequently  become  more  acute,  with  an  apparent 
increase  in  pain,  tenderness  and  hyperemia.  This  increased  reaction 
is  usually  followed  by  a  diminution  of  the  objective  evidences  of 
inflammation  until  in  many  instances  a  complete  restitution  to  the 
normal  is  brought  about.  In  order  to  understand  the  possible  sig- 
nificance and  therapeutic  importance  of  this  phenomenon  it  will  be 
necessary  to  briefly  review  our  present  conception  of  such  focal  re- 
actions. 

Ever  since  the  tuberculins  were  introduced  early  in  the  nineties 
the  concept  of  the  focal  reaction,  the  "Herd  Reaktion,"  at  the  site 
of  the  inflammatory  lesion  has  been  so  closely  associated  with  the 
diagnostic  and  the  therapeutic  principles  of  the  tuberculin  as  hypothe- 
cated by  Koch  that  the  field  has  been  limited  largely  to  a  con- 
sideration of  this  particular  disease.  This  view  of  the  focal  reaction, 
exemplified,  let  us  say,  in  a  local  disease  such  as  lupus  or  an  apical 
involvement,  needs  no  further  elucidation.  By  some  the  term  "local 
reaction"  is,  however,  used  synonymously;  it  should  of  course  be 
reversed  for  those  reactions  that  occur  at  the  site  of  the  injection 
of  the  tuberculins. 

By  common  consent  we  may  assume  that  positive  local  and  gen- 
eral reactions  are  regarded  as  corroborative  evidence  that  at  some 
time  the  organism  has  been  infected  with  tubercle  bacilli;  to  the 
focal  reaction  we  generally  attach  greater  significance  in  so  far  that 
the  observation  of  the  focal  reaction  following  tuberculin  injection 
is  regarded  as  proof  not  only  of  infection  but  of  activity  as  well.  It 
is  regarded  as  strictly  specific  in  the  sense  that  only  tuberculous 
processes  respond  to  tuberculin  injections.  On  this  assumption  the 

70 


THE  FOCAL  REACTION  71 

immunologists  have  elaborated  theories  to  picture  the  processes  go- 
ing on  at  the  site  of  the  reaction.  According  to  Wassermann  and 
Bruck  the  reaction  takes  place  when  the  injected  tuberculin  joins 
with  an  "antituberculin"  at  the  focus  and  the  complement  is  bound 
by  these  two  reacting  bodies.  The  fixed  complement  is  then  able 
to  "digest"  the  focal  material  and  so  cause  the  well-known  lytic 
phenomena  that  we  associate  with  focal  activation.  Wolff-Eisner 
and  others  have  expressed  the  idea  that  all  the  tuberculin  manifesta- 
tions are  due  to  preformed  specific  "lysins."  These  break  up  the 
nontoxic  tuberculin;  only  the  tuberculin  so  altered  can  initiate  the 
various  reactions.  The  entire  mechanism,  according  to  the  humoral 
views,  depends  on  the  presence  of  lysins — i.e.,  "much  lysin — much 
reaction." 

As  a  matter  of  fact  little  or  no  evidence  has  been  put  forward 
to  support  this  humoral  theory,  but,  on  the  contrary,  much  convincing 
evidence  discrediting  it.  No  antibodies  of  the  kind  hypothecated 
have  been  demonstrated.  Nor  does  a  parallelism  exist  between  the 
local,  focal  and  general  reactions,  such  as  would  be  predicated  if 
the  reaction  were  a  humoral  one.  On  the  contrary,  while  a  general 
reaction  follows  in  the  wake  of  a  focal  reaction,  the  local  reaction 
is  under  these  circumstances  suppressed.  But  practically  every 
clinical  phenomenon  has,  nevertheless,  been  interpreted  according  to 
these  theories  with  resulting  confusion.  One  illustration  will  suffice. 
Menzer  noted  that  tuberculous  foci  would  respond  with  a  typical 
"Herd  Reaktion"  after  the  injection  of  a  streptococcus  vaccine  and  that 
tuberculous  patients  would  very  frequently  have  a  general  reaction. 
From  this  he  drew  the  conclusion  that  such  reactions  merely  indicated 
that  a  secondary  infection  with  streptococci  had  been  imposed  on  the 
focus  and  that  the  evidences  of  reaction  which  he  observed  merely 
confirmed  the  specific  concept. 

As  a  matter  of  fact  it  was  through  the  demonstration  of  the  focal 
or  "Herd  Reaktion"  that  the  theory  of  specificity  for  the  tuberculins 
gained  wide  credence.  We  fitted  a  theory  to  the  observation  and 
then  proceeded  to  interpret  every  clinical  observation  in  this  or  the 
related  fields  to  conform  to  our  theory.  Reasoning  in  a  vicious  circle 
retarded  the  study  of  actual  clinical  conditions  and  particularly  held 
back  the  proper  recognition  of  certain  factors  in  cellular  resistance 
which  are  of  great  importance  not  only  in  tuberculosis  but  in  in- 
flammation in  general. 

Inasmuch  as  experience  with  tuberculosis  is  common  to  every 
physician,  the  consideration  of  the  focal  reaction  in  the  tuberculous 
is  perhaps  of  greatest  interest  and  importance,  but  the  problem  is  so 
closely  bound  up  with  inflammatory  reactions  in  general  that  it  may 
be  permissible  to  include  certain  references  to  conditions  of  non- 
tuberculous  origin  in  this  discussion. 


72  PROTEIN  THERAPY 

Concerning  the  Specificity  of  Focal  Reactions.— Perhaps   the 

fact  that  the  focal  reaction  is  not  a  specific  reaction  must  first 
be  emphasized.  Practically  every  inflammatory  focus,  irrespective 
of  its  etiology,  will  react  (focal  activation)  to  tuberculin  as  well 
as  to  a  great  variety  of  other  agents,  chemical  or  biological  in 
character.  Investigators  in  tuberculosis  have  long  recognized  the 
fact  that  the  tuberculous  lesion  responds  with  a  focal  reaction  to  a 
variety  of  substances.  Baldwin  mentions  nucleoprotein,  nuclein,  al- 
bumoses,  cinnamic  acid,  cantharidin,  pilocarpin.  Fishberg  adds  potas- 
sium iodid  and  creosote.  But  the  recognition  that  nontuberculous 
inflammatory  foci  will  likewise  respond  to  such  agents  has  only  been 
discussed  in  recent  years.  Perhaps  the  paper  of  Schmidt  is  of 
greatest  value  in  this  connection. 

Schmidt  began  his  observations  on  the  Poncet  type  of  arthritis. 
This  tuberculo-toxic  form  of  disease  exhibits  a  well-marked  focal  re- 
action following  the  injection  of  tuberculin — that  is,  the  joint  be- 
comes more  painful,  and  swollen,  there  is  an  increased  limitation  of 
motion  and  the  tissues  become  hyperemic.  This  stage  is  later  fol- 
lowed by  improvement  in  the  clinical  picture  (the  negative  phase 
is  followed  by  a  positive  one),  the  end  results  usually  being  an 
improvement  over  that  obtaining  before  the  tuberculin  injec- 
tion. 

But  Schmidt  found  that  if  instead  of  injecting  tuberculin,  milk  was 
used,  he  obtained  exactly  the  same  reaction  at  the  site  of  the  lesion, 
during  the  same  period  of  time,  and  with  the  same  positive  phase 
following  in  the  wake  of  the  reaction  (i.  e.,  a  therapeutic  effect) .  Fur- 
ther, when  he  turned  to  nontuberculous  joint  lesions  and  injected 
minute  doses  (.001  gm.)  of  Old  Tuberculin  (relatively  rich  in  nonspe- 
cific proteins)  he  obtained  a  similar  focal  reaction. 

Classification  of  Focal  Reactions. — The  German  clinicians  have 
gathered  considerable  data  concerning  the  reactions  that  follow  milk 
injections  (used  merely  as  a  convenient  nonspecific  protein)  and 
Schmidt  has  arranged  the  following  groups  in  which  there  is  a  re- 
sponse with  a  typical  focal  reaction  following  milk  (and  other)  injec- 
tions: 

I.  Inflammatory  foci  of  infectious  origin. 

II.  Localized  inflammatory  processes  endogenous  or  traumatic  in 
origin. 

III.  Diatheses. 

I.  INFLAMMATORY  Foci  OF  INFECTIOUS  ORIGIN.— Classified  under 
the  first  group  we  include  pulmonary  foci  of  tuberculous  origin. 

Schmidt  and  Kraus,  Petersen,  Holler,  Dollken  and  others  have 
called  attention  in  recent  papers  to  this  phenomenon.  Proteoses, 
iodids,  milk,  nucleins  and  other  agents  will  bring  about  a  focal  re- 


THE  FOCAL  REACTION  73 

action  and  a  sharp  general  systemic  reaction.  Tuberculous  foci  in 
lymph  glands,  in  the  kidney  and  the  genito-urinary  tract  and  else- 
where respond  in  a  similar  manner.  Closely  related  we  find  the  effect 
on  leprous  lesions.  Josephson  describes  the  activation  of  a  case  of 
macular  leprosy  following  the  accidental  injection  of  a  relatively 
large  intravenous  dose  of  vaccine. 

Among  the  nontuberculous  inflammatory  foci  can  be  included  the 
tonsils  which  at  times  flare  up  after  a  nonspecific  injection.  Schmidt 
describes  such  a  case  in  which  a  milk  injection  activated  a  latent 
angina  with  the  coincident  appearance  of  mild  joint  pains.  Inflam- 
matory activation  can  be  observed  following  milk  injections  in  cases 
of  furunculosis  and  in  some  instances  more  than  the  usual  amount  of 
constitutional  reaction.  Thus  the  normal  diabetic  does  not  react 
with  a  temperature  rise  to  milk  injections,  but  if  suffering  from 
furuncles  will  frequently  do  so.  We  also  note  arthropathies,  the  nega- 
tive phase  of  which,  with  its  increased  pain,  swelling  and  limitation  of 
motion,  is  not  an  uncommon  clinical  observation  and  has  been  fully 
discussed  by  a  number  of  observers.  Inflammatory  foci  in  the  ap- 
pendix and  the  gall-bladder,  erysipelas,  inflammatory  lesions  of  the 
eye,  inflammatory  lesions  of  the  respiratory  tract,  of  the  female  adnexa 
and  the  male  genito-urinary  tract,  etc.,  are  also  found.  Schittenhelm 
observed  that  following  the  injection  of  typhoid  vaccine  old  fistulas 
would  show  an  increased  amount  of  secretion;  bronchiectatic  patients 
would  secrete  more  mucus;  chronic  appendiceal  lesions  would  become 
more  painful  and  tender,  etc. 

The  activation  of  quiescent  malarial  foci  has  assumed  diagnostic 
importance  and  will  be  more  fully  discussed.  Papules  of  syphilitic 
origin  react  with  an  increased  hyperemia  just  as  do  other  inflamma- 
tory foci. 

In  a  general  way  one  can  make  the  statement  that  any  circum- 
scribed inflammatory  process  irrespective  of  its  bacterial  etiology  or 
its  location  will  frequently  light  up  with  a  typical  focal  reaction  after 
a  nonspecific  injection  and  usually  within  24  hours  after  the  injection. 
Of  these  various  processes  tuberculous  lesions  are  perhaps  more  sen- 
sitive because  of  a  more  profound  sensitization  of  the  tissue  cells  of 
the  host  against  protein  in  general — as  suggested  by  a  recent  dis- 
cussion by  Wolff-Eisner. 

II.  LOCALIZED  INFLAMMATORY  PROCESSES  ENDOGENOUS  OR  TRAU- 
MATIC IN  ORIGIN. — In  this  category  must  be  placed  certain  of  the 
toxic  forms  of  arthritis,  such  as  the  Poncet  type,  as  well  as  gout.  In- 
flammatory lesions  of  the  kidney,  and  inflammatory  lesions  of  the  eye, 
including  iritis,  albuminuric  retinitis,  etc.,  are  also  among  the  local- 
ized processes.  Healing  fractures,  such  as  Dollken  has  described, 
respond  with  a  typical  focal  reaction.  Neuritis  is  to  be  included  in 
this  group. 


74  PROTEIN  THERAPY 

III.  LOCALIZED  LESIONS  ON  A  BASIS  OF  A  DIATHESIS. — Using  this 
term  in  the  broader  significance  as  defined  by  Pfaundler,  the  follow- 
ing conditions  might  be  included: 

The  lancinating  pains  of  tabes  which  at  times  follow  on  nonspe- 
cific injections,  as  well  as  an  occasional  gastric  crisis. 

In  paresis  the  psychic  state  may  be  decidedly  disturbed  and  the 
disease  manifestations  become  more  apparent  following  nonspecific 
injections.  This  is  not  an  uncommon  experience  in  the  treatment  of 
paresis  as  outlined  by  v.  Jauregg.  In  epilepsy  an  attack  may  be 
inaugurated  if  a  large  dose  of  a  nonspecific  agent  is  administered 
(Adrenalin-Benedek) ,  just  as  in  chronic  alcoholics  an  attack  of  de- 
lirium tremens  may  follow  such  an  injection. 

In  this  sense  we  may  consider  that  a  latent  symptomatology  may 
abruptly  unfold  its  various  manifestations  following  injections  of 
protein. 

Activating  Agents. — We  must  for  a  moment  stop  to  consider  the 
agents  that  are  involved  in  eliciting  this  nonspecific  reaction.  Because 
of  the  early  work  in  this  field  we  commonly  regard  the  nonspecific  re- 
action as  one  that  follows  the  intravenous  injection  of  a  vaccine — let  us 
say  typhoid  vaccine,  or  such  protein  derivatives  as  proteoses,  or  more 
recently  the  use  of  milk  (given  intramuscularly).  Not  only  do 
such  injections  bring  about  the  reaction  and  the  focal  activation, 
but  certain  general  biological  alterations  such  as  coincident  but  remote 
disease  processes,  metabolic  alterations  of  endocrine  origin,  fatigue,  in- 
testinal intoxication,  blood-letting,  Roentgen  exposures,  trauma,  altera- 
tions in  the  skin,  chilling, — counterirritation — as  well  as  certain  drugs 
bring  about  exactly  the  same  focal  alteration.  The  activation  of  a 
tuberculosis  by  an  angina,  a  remote  trauma,  the  menstrual  cycle,  by 
influenza  or  measles;  the  provocation  of  a  malarial  paroxysm  (the 
result  of  a  splenic  focal  activation)  by  an  intercurrent  disease,  by 
prophylactic  vaccination,  by  severe  fatigue,  long  railroad  journeys, 
overheating,  exposure  to  intense  light,  chilling  or  drenching,  dietery 
fault,  alcoholic  excess  and  the  various  other  factors  that  the  experi- 
ence of  the  war  has  brought  to  light;  the  focal  reaction  about  latent 
arthritic  lesions  which  Pemberton  has  described  after  irradiation,  ra- 
dium, thyroid  extract,  excitement,  etc.;  the  classical  activation  of 
gonorrheal  processes  by  a  variety  of  seemingly  remote  causes;  the 
precipitation  of  lancinating  pains  or  a  tabetic  crisis  following  a 
"cold";  the  origin  of  a  delirium  tremens  following  a  trauma;  the 
onset  of  pellagrous  symptoms  after  exposure  to  sunlight;  these  are 
but  a  few  examples  of  a  universal  phenomenon  heretofore  com- 
monly observed  but  not  recognized  as  having  a  common  back- 
ground. 

It  is  very  probable  that  many  puzzling  clinical  manifestations 
,and  unusual  features  of  certain  diseases  may  readily  be  explained 


THE  FOCAL  REACTION  75 

and  will  appear  in  a  very  simple  light  if  we  keep  in  mind  the  basic 
idea  that  the  particular  symptom  complex  under  study  may  be  due 
solely  to  the  activation  of  an  inflammatory  focus  of  exogenous  or 
endogenous  origin  in. the  manner  of  the  "Herd  Reaktion."  Many 
of  the  curious  metabolic  disturbances  at  times  associated  with  dia- 
betes and  nephritis  can  readily  be  accounted  for  on  such  a  basis. 
Even  pharmacological  study  reveals  evidence  of  this  same  nonspe- 
cific effect  on  inflammatory  lesions.  Thus  the  commonly  observed 
Jarisch-Herxheimer  reaction  (the  flaring  up  of  syphilitic  skin  lesions 
under  specific  treatment)  is  an  example,*  while  the  activation  of  a 
tuberculous  lesion  after  iodid  medication  is  an  even  older  observa- 
tion. So,  too,  we  may  get  an  ulcerative  catarrhal  condition  when  a 
uremic  colitis  is  carelessly  treated  with  calomel,  while  Koniger,  in 
a  recent  paper,  has  even  been  able  to  demonstrate  that  the  anti- 
pyretics, when  given  in  proper  interval  doses,  all  bring  about  a 
nonspecific  "plasmaactivation"  and  must  therefore  be  included 
among  those  agents  potentially  capable  of  bringing  about  focal  re- 
actions. 

This  widening  of  the  concept  of  the  focal  reaction  makes  it  of 
decided  importance  in  the  special  pathology  of  internal  diseases. 
Acute  conditions  may  often  be  nothing  more  than  the  exacerbation  of 
heretofore  latent  processes  of  definite  bacterial  etiology  or  perhaps 
of  a  diathesis.  On  this  basis  can  be  explained  the  fact  that  children 
often  respond  with  a  severe  angina  to  a  fault  in  the  diet;  that  an  ap- 
pendicitis will  become  acute  following  an  angina,  a  remote  trauma 
or  an  injection  of  a  prophylactic  dose  of  vaccine;  that  a  gastric  crisis 
or  lancinating  pains  will  commence  after  some  remote  exciting  cause 
or  an  asthmatic  attack  occur  under  the  influence  of  some  meteor- 
ological or  climatic  alteration. 

In  many  ways  this  basis  for  the  immediate  etiology  of  an  ap- 
pendiceal  inflammation  or  the  flare-up  of  a  gall  bladder  seems  more 
rational  than  the  suggestion  that  we  deal  with  a  specific  localization 
of  bacteria,  so  altered  in  their  metabolic  demands  and  peculiarities 
that  they  will  grow  only  in  certain  tissues.  This  latter  hypothesis 
which  Rosenow  has  developed  ignores  the  fact  that  in  the  history  of 
acute  inflammatory  processes  one  may  note  a  preceding  history  of 
remote  trauma  or  systemic  shock  of  some  kind  or  a  metabolic  dis- 
turbance of  nonbacterial  origin  just  as  often  if  not  more  frequently 
than  a  history  of  a  preceding  infection. 

The  Diphasic  Character  of  the  Focal  Reaction.— While  in  the 
preceding  pages  the  attention  has  been  centered  on  the  fact  that 
a  variety  of  agents  may  be  used  to  elicit  the  tuberculin  reac- 

*  The  so-called  sensitization  of  the  skin  to  metallic  colloids  is  similar  in 
character.  Hift  found,  for  instance,  that  if  he  injected  electrargol  intravenously 
after  having  injected  small  amounts  into  the  skin  previously,  the  involuted  skin 
papules  would  again  flare  up. 


76  PROTEIN  THERAPY 

tion  (focal)  one  can  also  determine  that  nontuberculous  processes 
respond  with  a  focal  reaction  to  tuberculin.  Schmidt  illustrates  this 
with  two  convalescent  cases  of  polyarthritis  which  had  been  free  from 
fever  and  local  symptoms,  pain,  etc.,  for  over  two  weeks.  Both 
cases  on  receiving  0.001  gm.  O.T.  subcutaneously,  responded  with 
severe  pain  in  the  joints  previously  involved,  slight  periarticular  swell- 
ing and  some  limitation  of  motion;  the  duration  of  the  reaction  was 
of  course  transient.  I  have  had  occasion  to  repeat  these  observations 
of  Schmidt's  and  in  a  considerable  percentage  of  the  cases  studied 
I  have  found  that  the  observation  holds  true.  In  processes  that  can 
be  observed  at  the  exterior  surfaces  of  the  body,  particularly  in  the 
violent  activation  of  chronic  inflammatory  lesions,  one  can  observe 
the  dualistic  nature  of  the  reaction — and  this  is  of  paramount  im- 
portance in  the  therapeutic  application  of  the  reaction — a  negative 
phase  in  the  sense  that  the  tissue  is  altered  more  from  the  normal  than 
heretofore,  i.e.,  the  evidences  of  inflammation  are  increased — pain  and 
swelling  augmented,  function  impaired,  etc.;  then  a  positive  phase 
during  which  there  is  a  progressive  diminution  of  the  inflammation 
until  the  preinjection  status  is  again  reached  or  passed,  the  balance 
swinging  in  this  direction  until  practically  normal  conditions  are  re- 
stored. Augmentation  of  the  inflammation  is  followed  by  a  diminu- 
tion until  healing  is  accomplished — the  pendulum  swings  from  one 
side  to  the  other  in  the  wave-like  curve  that  we  find  expressed  so 
commonly  in  many  biological  processes — in  the  opsonin  curve,  the 
antiferment  curve,  in  the  leukocytic  response,  in  the  coagulation 
mechanism,  in  cell  permeability,  all  indicative  of  the  exquisite  lability 
of  the  balance  that  exists  in  living  protoplasm. 

The  focal  reaction  has  its  counterpart  in  the  general  reaction  of 
the  patient  that  usually  accompanies  the  reaction,  occasionally  in 
the  tuberculous,  more  often  in  acute  infections  and  corresponds 
obviously  with  Weichardt's  period  of  "plasmaactivation."  This  dual- 
ity observed  in  both  the  focal  reaction  and  the  general  reaction  is 
of  utmost  therapeutic  interest. 

It  is  reasonable  that  we  would  seek  to  make  the  negative  phase, 
representing  an  augmentation  of  the  inflammatory  process  as  short 
as  possible  and  the  positive  phase  relatively  intense  and  protracted. 
But  the  possibility  arises,  based  on  clinical  observation,  that  the  de- 
gree and  extent  of  the  positive  phase  (curative)  is  closely  dependent 
upon  and  correlated  with  the  negative  phase,  i.e.,  that  their  relative 
intensity  is  proportional.  We  may  conceive  the  negative  phase,  which 
in  point  of  time  always  precedes  the  positive  one,  as  an  exogenously 
produced  irritative  process,  the  positive  one,  on  the  other  hand,  as  an 
endogenous!^  prepared,  more  or  less  physiological  process  of  vital 
repair.  Clinically,  as  far  as  focal  reactions  are  concerned  (as  for 
instance  in  tuberculosis) ,  it  is  chiefly  the  negative  phase  that  comes 
to  our  attention  in  the  form  of  the  activation  phenomena  with  whioh 


THE  FOCAL  REACTION  77 

we  are  familiar.  But,  from  analogous  studies  in  focal  reactions  else- 
where it  must  be  assumed  that,  with  proper  dosage,  the  positive  phase 
and  the  increased  tendency  to  healing  follows  about  the  lung  focus 
just  as  it  does  about  a  joint  lesion  that  can  be  objectively  studied. 
In  this  duality  of  the  reaction  lies  the  usefulness  of  the  focal  reaction 
as  a  therapeutic  measure. 

Mechanism  of  Focal  Reaction. — VASCULARIZED  INFLAMMATORY 
Foci. — During  the  course  of  the  past  five  years  we  have  become  fa- 
miliar with  the  biological  alterations  that  take  place  in  the  organism 
after  tuberculin  injections  as  well  as  after  the  so-called  nonspecific 
agents.  These  changes,  described  in  the  preceding  chapter,  are  nu- 
merous and  complex  but  the  more  important  can  be  placed  in  two 
groups:  (1)  those  that  deal  with  cellular  stimulation,  and  those 
(2)  that  result  primarily  from  alterations  in  the  permeability  of  the 
cells. 

The  former  have  been  broadly  included  by  Weichardt  under  the 
term  "Plasmaactivation."  Under  the  stimulus  of  moderate  doses  of 
nonspecific  agents  cellular  activity  is  markedly  increased.  This  finds 
its  expression  in  increased  secretory  activity  of  gland  cells,  increased 
activity  of  muscle  cells  (myocardium),  increased  activity  of  leu- 
kocytes (phagocytosis),  etc.  The  changes  that  take  place  in  the 
permeability  of  the  cell  membrane  have  been  studied  by  Luithlen,  by 
Starkenstein  and  others  and  represent  a  decidedly  diphasic  phenomenon. 
The  permeability  of  (the  capillaries  is  first  increased  as  evidenced  in 
the  great  increase  in  the  lymph  flow  and  in  the  concentration  of  the 
blood;  the  permeability  of  the  tissue  cells  is  increased — with  a  re- 
sulting outpouring  of  enzymes,  of  fibrinogen  and  prothrombin,  of 
immune  bodies,  etc.;  the  increased  permeability  of  the  nerve  cells  is 
associated  with  a  lowering  of  the  threshhold  for  nervous  impulses 
and  becomes  manifest  clinically  in  increased  susceptibility  to  pain, 
general  irritability,  headache,  etc.  When  this  first  phase  has  passed 
compensation  takes  place  in  a  lessened  permeability  of  the  cells,  with 
effects  that  are  to  be  anticipated — lessened  susceptibility  to  intoxi- 
cation, lessened  nervous  irritability — lessened  exudation — a  lowering 
of  enzyme  concentration,  etc. 

Numerous  other  observations  have  been  made  that  are,  in  my 
opinion,  subordinate  in  interest  to  these  two  fundamental  alterations 
in  the  permeability  of  the  cell  membranes  and  the  general  stimulation 
of  the  protoplasm. 

With  these  considerations  in  mind  we  can  approach  the  study  of 
the  mechanism  possibly  involved  in  the  focal  reaction  about  inflam- 
matory tissues  from  a  relatively  simple  point  of  view. 

In  an  inflammatory  focus  supplied  with  highly  vascularized  gran- 
ulation tissue  the  systemic  effects  of  a  tuberculin  injection  or  the  in- 
jection of  a  nonspecific  agent  will  bring  about  (1)  an  increase  in 
the  exudation  of  fluids — with  increased  redness  and  swelling  because 


78  PROTEIN  THERAPY 

of  the  transient  increase  in  the  permeability.  With  this  there  is  as- 
sociated (2)  an  increase  in  pain  and  tenderness  both  because  of  the 
increased  pressure  and  the  lowering  of  the  threshold  or  nerve  stimuli. 
There  will  be  (3)  increased  digestion  at  the  focus  of  inflammation;  if 
there  is  no  necrotic  material  present  in  the  focus  there  may  be  no 
evidence  of  increased  systemic  intoxication;  if  the  amount  of  necrotic 
material  is  large  there  will  first  result  an  increase  in  systemic  in- 
toxication when  the  material  split  down  is  absorbed;  with  more 
complete  digestion  at  the  focus,  complete  detoxication  may  re- 
sult. 

All  these  changes  we  associate  with  the  focal  activation  that  follows 
nonspecific  injections.  To  these  must  be  added  another  factor  and  one 
more  complex.  It  concerns  the  observation  that  any  cell  previously 
involved  in  an  inflammatory  reaction  responds  to  stimuli  of  all  kinds 
more  readily  than  a  normal  cell.  Objectively  we  can  observe  this  in 
involuting  skin  lesions. 

The  augmentation  in  the  inflammatory  reaction  which  we  have 
induced  brings  with  it,  as  we  have  seen,  an  increased  lymph  flow. 
Coincident  with  it  there  has  been  a  relative  increase  in  enzymes — 
protease,  ereptase  (peptidase)  lipase,  etc., — an  increase  in  the  anti- 
bodies (if  the  patient  has  been  previously  immunized  or  if  the  infection 
has  existed  for  some  time),  an  increase  in  the  leukocytes  (after  the 
initial  leukopenia),  together  with  an  increase  in  their  phagocytic 
activity,  and  an  increased  coagulability  of  the  blood.  The  antibody, 
the  leukocytic  and  the  enzyme  alterations  must  exert  a  considerable 
effect  on  an  infecting  agent  as  well  as  on  the  removal  of  necrotic 
material;  the  tendency  toward  restitution  to  the  normal  would  be 
enhanced.  It  is  this  phase  that  we  see  in  the  so-called  second  or 
positive  phase.  Its  coincident  constitutional  effect  that  we  witness  in 
the  euphoria,  in  the  lowering  of  the  temperature,  improvement  of  the 
circulation,  etc.,  is  due  to  at  least  three  factors — (a)  the  destruction 
of  toxic  material  at  the  focus  after  the  primary  increase  in  digestive 
activity,  (b)  lessened  susceptibility  of  the  cells  of  the  body  to  intox- 
ication (due  to  the  lessened  permeability),  and  (c)  actual  protoplasmic 
stimulation  (partly  from  the  nonspecific  or  specific  agent  injected, 
partly  from  the  toxic  material  liberated  from  the  inflammatory 
focus).  This  later  factor  varies  greatly  and  the  clinical  estima- 
tion of  the  possible  degree  of  this  variation  requires  experience  and 
care. 

TUBERCULOUS  Foci. — Turning  from  the  vascularized  inflammatory 
focus  to  the  tubercle  we  find  other  conditions.  In  Schmidt's  paper  the 
view  emphasized  is  that  in  the  general  tuberculin  reaction  we  are  most 
likely  dealing  with  both  specific  and  nonspecific  factors,  an  opinion 
similar  to  that  which  we  have  expressed  in  a  previous  paper.  Schmidt 
has  stated  this  concept  as  follows  "But  it  is  probable  that  in  the 
question  of  specificity  or  nonspecificity,  the  placing  of  the  one  versus 


THE  FOCAL  REACTION  79 

the  other  is  a  mistake — that  it  should  rather  be  the  examination  of 
specificity  and  nonspecificity,  i.e.,  that  both  factors  enter  into  the 
reaction  and  it  should  be  determined  how  far  each  factor  is  involved." 
Our  concept  has  been  that  while  the  systemic  reaction  was  largely 
nonspecific  in  that  the  means  used  to  elicit  it  need  not  be  specific,  the 
focal  reaction  itself,  once  initiated,  brings  in  its  wake  a  truly  specific 
stimulation  because  the  inflammatory  reaction  may  lead  to  the  libera- 
tion of  disintegrating  bacterial  material  and  possibly  even  living 
bacteria.  These  substances  would  secondarily  lead  to  a  specific 
response  on  the  part  of  the  body.* 

At  least  three  factors  must  be  considered  in  the  mechanism  of 
the  focal  reaction  in  tuberculosis,  apart  from  the  anatomical  pecu- 
liarities of  the  tubercle  as  contrasted  with  other  inflammatory  proc- 
esses. 

Specific. — These  concern  primarily  a  tissue  sensitization  against 
tuberculoprotein,  strictly  specific  in  character,  cellular  in  its  localiza- 
tion and  not  necessarily  associated  with  the  older  conception  that  was 
built  up  about  the  humoral  antibodies.  Indeed  I  am  of  the  opinion 
that  the  latter  may  very  well  be  relegated  to  a  subordinate  position 
in  the  field  of  tuberculosis.  Inasmuch  as  this  subject  of  tissue  sensi- 
tization has  been  extensively  discussed  by  a  number  of  workers,  par- 
ticularly by  Krause  in  this  country,  it  will  be  unnecessary  to  enter 
into  this  phase  here. 

General  Hyper  sensitiveness  of  the  Tuberculous. — Granted  that 
the  tuberculous  focus  responds  to  smaller  doses  of  tuberculin  than  does 
a  focus  of  nontuberculous  origin,  how  are  we  to  account  for  the  fact 
in  view  of  the* practical  avascularity  of  the  tubercle?  That  the  speci- 
ficity concept  of  the  immunologist  will  no  longer  explain  the  accumu- 
lated evidence  is  to-day  acknowledged,  and  Wolff-Eisner  accepts  the 
change  in  our  viewpoint  in  a  recent  paper.  I  can  but  very  briefly 
enter  into  the  more  lengthy  theoretical  discussion  that  he  presents. 
He  first  emphasizes  the  relation  that  exists  between  the  diet  and 
exudative  diathesis,,  defining  this  latter  condition  as  due  to  the  ab- 

*  It  is  this  factor  that  Klemperer  in  his  recent  criticism  of  Schmidt's  claims 
has  ignored.  Klemperer  found  that  following  milk  injections  in  tuberculous 
patients  they  did  not  become  resistant  to  following  injections  of  tuberculin  and 
vice  versa.  Injections  of  milk  bring  about  a  febrile  reaction  in  a  large  per- 
centage of  individuals;  they  bring  about  a  focal  reaction  in  only  a  limited 
number  of  tuberculous  patients,  just  as  tuberculin  injections  are  followed  by 
focal  reactions  in  an  irregular  number.  If  the  injection  of  milk  brings  about 
(in  the  tuberculous  individual)  a  systemic  reaction  without  focal  activation,  a 
following  injection  of  tuberculin  may  still  give  rise  to  a  typical  general  reaction. 
If,  on  the  other  hand,  a  focal  reaction  results,  either  by  specific  or  nonspecific 
means,  local  tuberculin  reactions  are  suppressed  for  some  time  following  the 
general  reaction.  Klemperer  is,  however,  quite  justified  both  in  his  criticism  of 
the  local  reactions  reported  by  Schmidt  following  milk  injections  in  tuberculous 
patients  and  in  his  views  concerning  the  possible  harm  from  activation  of  tuber- 
culous foci  following  milk  injections. 


80  PROTEIN  THERAPY 

sorption  of  proteins  and  protein  fragments  insufficiently  degraded  in 
the  intestinal  tract,  i.e.,  a  protein  sensitization.  He  then  develops  the 
more  or  less  definite  association  of  the  exudative  diathesis  and  spas- 
mophilia  with  scrofula;  while  he  does  not  regard  the  scrofula  as  the 
cause  of  the  diathesis,  he  inclines  to  the  definition  of  Feer  that 
"scrofula  is  tuberculosis  on  the  basis  of  an  exudative  diathesis." 
Wolff-Eisner  is  inclined  to  the  view  that  in  tuberculosis  there  is  evi- 
dence of  an  exudative  diathesis  with  sensitization  against  tuberculin 
and  also  against  proteins  in  general.  This  latter  which  is  nonspecific 
and  general  in  character  accounts,  in  his  estimation,  for  many  of  the 
evidences  of  similarity  in  the  clinical  course  of  tuberculosis  and  those 
observed  in  an  exudative  diathesis.  Not  only  is  scrofula  "tuberculosis 
on  the  basis  of  a  diathesis"  but  the  tuberculous  lesion  itself,  involving 
as  it  does  the  prolonged  absorption  of  partially  split  proteins  from  the 
necrotic  foci,  may  ultimately  bring  in  its  train  symptoms  that  are 
commonly  regarded  as  due  to  a  diathesis.  As  such  he  regards  the 
changes  observed  in  the  cornea,  skin  lesions  such  as  the  tuberculids, 
the  decided  alterations  in  the  reactivity  of  the  sympathetic  and  central 
nervous  systems  to  which  Moro,  Pottenger  and  Ferranini  have  called 
attention.  While  we  have  been  familiar  with  the  increased  nervous 
lability  of  the  tuberculous  individual  for  a  long  time,  we  have  failed 
to  grasp  the  dependence  of  the  increased  irritability  on  the  general 
hypersensitiveness  to  proteins.  Not  only  does  this  nervous  irritability 
indicate  the  close  parallelism  to  the  diathesis  of  the  child,  the  tendency 
to  effusion  is  also  evident  in  the  tuberculous  patient — one  has  but  to 
call  to  mind  the  common  appearance  of  pleural,  peritoneal  and  joint 
effusions.  The  alteration  in  the  vasomotor  stability  also  finds  its 
expression  in  the  frequent  appearance  of  urticarial  eruptions  after 
tuberculin  injections. 

It  will  be  recalled  from  the  previous  discussion  of  the  effects  of 
nonspecific  injections  on  the  permeability  of  vascular  endothelium  that, 
depending  on  the  dosage  or  the  degree  of  irritation  (or  stimulation  if 
we  wish  to  use  that  term)  there  may  result  either  an  increase  or  a 
decrease  in  the  permeability.  We  may  expect  that  the  effect  of  the 
tuberculin  (or  the  living  virus)  will  also  find  some  expression  in 
changes  in  the  permeability  in  one  direction  or  another.  According  to 
Wolff-Eisner  we  find  the  clinical  demonstration  of  this  experimental 
observation  in  the  effect  of  the  tuberculous  invasion  of  lung  tissue, 
where  in  one  instance  we  find  an  exudative  change,  in  another  an 
indurative  process. 

Plasmaactivation. — The  third  factor  involves  the  consideration  of 
the  effects  which  any  nonspecific  provocative  agent  would  have  on  an 
inflammatory  lesion  such  as  the  tubercle;  the  tubercle  would  react  as 
any  seminecrotic  focus  of  other  etiology  would  react  were  it  not  for  the 
fact  that  the  tubercle  is  practically  avascular.  Tubercles  react  to 
nonspecific  injections  (or  to  nonspecific  stimuli  of  other  origin)  only 


THE  FOCAL  REACTION  81 

when  they  are  of  the  exudative  type  or  when  the  connective  tissue 
delimitation  of  the  tubercle  is  either  incomplete  or  exceedingly  labile. 
It  is  to  be  recalled  that  as  one  of  the  results  of  plasmaactivation 
proteolytic  enzymes  appear  in  the  serum  and  in  inflammatory  foci  and 
that  the  polymorphonuclear  leukocytes  are  increased  in  number  and 
in  activity.  The  augmented  digestive  activity  results  in  a  loosening 
of  the  connective  tissue  defense  of  the  tubercle.  If  sufficiently  intense 
a  typical  focal  reaction — activation-absorption  of  necrotic  material 
and  systemic  reaction — can  result  in  this  way,  just  as  after  stimula- 
tion due  to  specific  tuberculins. 

The  Therapeutic  Application  of  the  Focal  Reaction.— Schmidt  is 
of  the  opinion  that  the  local  reaction,  elicited  by  means  of  specific 
or  nonspecific  agents  (such  as  milk),  is  of  definite  value  in  tuber- 
culosis, and  together  with  Kraus  cites  some  twenty-odd  cases  to  sup- 
port his  view.  While  it  is  of  course  not  to  be  denied  that  in  a  very 
limited  number  of  cases  this  may  be  true,  we  are  of  the  opinion  that 
the  tubercle  offers  a  decided  exception  to  the  general  rule  that  the 
active  stimulation  of  a  chronic  inflammatory  focus  is  of  therapeutic 
value.  We  have  pointed  out  that  for  vascularized  inflammatory  lesions 
such  stimulation  affords  a  rational  method  of  therapy.  In  the  tubercle 
we  deal  with  the  constant  danger  that  the  limitation  of  the  lesions  by 
means  of  the  connective  tissue  encapsulation  may  be  sufficiently  dis- 
organized that  an  extension  of  the  process  and  irreparable  injury  may 
result.  Irrespective,  therefore,  of  the  theoretical  probabilities  that 
therapeutic  focal  activation  may  be  beneficial,  in  the  tuberculous  lesion 
it  is  a  hazardous  procedure  (Lewin).  Before  leaving  the  subject  it 
must  be  pointed  out  that  nonspecific  stimulation  of  the  tuberculous 
patient  (not  involving  focal  reactions)  has  been  found  very  useful  both 
with  certain  drugs  (and  these  include  the  commonly  accepted  ones 
such  as  creosote,  succinates,  arsenicals,  etc.),  as  well  as  with  serum 
injections  such  as  Czerny  and  Eliasberger  have  recently  reported. 
That  the  milder  nonspecific  injections  seem  to  have  a  decidedly  stimu- 
lating effect  on  the  metabolism  of  infants  has  been  previously  reported. 
(Plantenga,  etc.) 

The  peculiar  therapeutic  importance  that  attaches  to  the  diphasic 
character  of  the  focal  reaction  has  been  previously  discussed.  Through 
the  existence  of  inflammatory  foci  in  various  organs  the  omnicellular 
stimulation  by  means  of  the  various  nonspecific  agents  (the  ergotropie 
of  v.  Groer)  becomes  to  a  certain  extent  an  organotropie.  It  is  in  this 
sense  that  we  must  consider  the  effect  of  the  treatment  of  paresis  by 
means  of  tuberculin  injections  and  similar  therapeutic  measures.  A 
combined  therapy  of  nonspecific  and  etiotropic  agents  may  be  of 
value,  and  experiments  in  this  direction  have  been  reported  by  Kyrle 
and  Scherber,  who  have  used  milk  injections  in  conjunction  with  mer- 
cury in  the  treatment  of  syphilis,  or  the  use  of  milk  injections  and 
salicylates  in  the  treatment  of  arthritis,  the  use  of  milk  injections  and 


82  PROTEIN  THERAPY 

luminal  in  the  treatment  of  epilepsy,  or  the  treatment  of  lupus  with 
tuberculin  and  salvarsan  (the  latter  in  this  case  serving  as  the  non- 
specific agent) .  Our  older  method  of  treating  syphilis  with  alternating 
courses  of  mercury  and  iodids  made  use  of  this  form  of  a  combined 
specific  and  nonspecific  method  for  many  years;  the  nonspecific  effect 
of  the^iodids  is,  however,  not  marked ;  the  effect  is  to  be  sought  rather 
in  the  effect  of  the  iodids  in  facilitating  the  diffusion  of  the  mercury. 
If  a  more  active  agent  than  iodids  is  used  the  mercurialization  of  the 
patient  can  be  very  rapidly  brought  about. 

While  therefore  the  local  reaction  has  therapeutic  possibilities 
which  should  be  studied  and  developed,  we  must  always  keep  in  mind 
that  there  are  possibilities  for  harm  in  the  reaction.  Just  as  during  a 
malarial  attack  a  syphilis  may  flare  up  (Noel) ,  so  a  tuberculous  lesion 
may  become  activated  after  a  salvarsan  injection  or  a  prophylactic 
vaccination.  Veilchenblau  has  described  an  apoplectic  attack  (old 
syphilitic)  in  a  patient  who  was  given  an  arthigon  injection  for  a 
complicating  gonorrhea. 


CHAPTER  V 

THEORIES  CONCERNING  THE  MECHANISM  OF  THE 
REACTION 

When  the  clinical  results  of  nonspecific  therapy  were  first  made 
known  we  were  quite  at  a  loss  to  account  for  the  results  obtained.  It 
represented  empiricism  pure  and  simple,  and  being  diametrically  at 
variance  with  current  conceptions  of  immunity  and  resistance  it  was 
to  be  expected  that  scientifically  trained  physicians  would  be  decidedly 
skeptical — the  more  so  since  the  heroic  measures  at  first  utilized  to 
bring  about  the  reaction  were  not  without  inherent  danger.  But  when, 
with  increasing  evidence  of  clinical  success,  the  importance  of  the 
reaction  could  no  longer  be  ignored  we  had  to  seek  for  some  explana- 
tion to  account  for  the  therapeutic  benefit  even  though  we  had  to 
recast  our  entire  conception  of  the  mechanism  of  recovery  from  disease. 

The  evidence  of  the  reaction  of  the  patient — the  chill,  fever,  sweat 
and  leukocytosis — might  all  be  assumed  to  have  some  bearing  on  the 
therapeutic  result.  We  knew  from  experience  that  after  a  severe  chill 
the  septic  case  might  have  a  defervescence  and  recover  from  the  infec- 
tion. We  knew  that  an  intercurrent  febrile  course  might  favorably 
influence  a  preexisting  disease  process.  We  knew  that  a  thorough 
sweat  would  frequently  relieve  the  symptomatology  of  many  diseases. 
And  the  importance  of  the  reactive  leukocytosis  in  resistance  and  its 
significance  in  prognosis  had  been  sufficiently  impressed  upon  us  in  a 
number  of  diseases,  especially  in  pneumonia.  But  none  of  these 
observable  reactions  on  the  part  of  the  patient  seemed  in  itself 
sufficient  to  account  for  the  striking  effect  that  occasionally  followed 
the  nonspecific  injections. 

In  examining  the  published  experience  of  a  number  of  clinics  it  was 
found  to  be  a  common  observation  that  nonspecific  therapy  gave  best 
results  if  used  early  in  a  disease  process.  It  was  also  noted  that  the 
beneficial  effect  from  the  reaction  depended  to  a  considerable  extent  on 
its  severity;  later  injections,  to  which  the  patient  responded  with 
diminished  severity,  were  less  efficacious. 

These  two  clinical  observations  proved  a  valuable  clew  to  a  partial 
solution  of  the  mechanism  that  underlies  nonspecific  therapy.  The 
fact  that  the  most  marked  therapeutic  effect  could  be  attained  early 
in  disease  rather  than  late  led  to  the  realization  that  in  injecting  the 

83 


84  PROTEIN  THERAPY 

various  substances  we  were  stimulating  the  organism — late  in  dis- 
ease, in  an  exhausted  patient,  stimulation  would  naturally  be  un- 
availing. The  fact  that  the  degree  of  stimulation  and  reaction  de- 
termined the  therapeutic  effect  was  evidence  of  one  of  the  frequently 
observable  biological  balances  in  which  the  end  reaction  (recovery  in 
this  case)  seems  proportionately  greater  than  the  stimulus  (intoxi- 
cation) . 

Weichardt 's  Theory. — Weichardt,  whose  work  with  protein  in- 
toxication and  fatigue  intoxication  is  well  known,  based  his  explana- 
tion of  the  nonspecific  reaction  on  these  two  basic  observations  and 
the  term  "Plasmaactivation"  or  "Omnicellular  Plasmaactivation"  with 
which  Weichardt  has  sought  to  designate  the  mechanism  involved  in 
nonspecific  therapy  is  perhaps  a  satisfactory  one  in  that  we  may 
include  under  it  the  many  possible  and  probable  alterations  that  are 
inaugurated  by  the  reaction  without  limiting  our  conception  to  any 
one  feature.  Bessau  has  but  recently  pointed  out  that  the  favorable 
therapeutic  action  corresponds  to  Pfeiffer's  older  conception  of  means 
to  increase  the  resisting  power  of  the  organism,  for  Pfeiffer  showed 
that  a  variety  of  interventions  in  acute  infections  induced  an  im- 
mediate increase  in  the  resisting  power. 

Inasmuch  as  few  investigators  in  this  field  of  research  have  had  the 
experience  that  Weichardt  has  had,  it  may  be  well  to  go  back  for  a  mo- 
ment to  the  fundamental  observations  that  underlie  his  conception  of 
"Plasmaactivation/-7  Gamaleia,  in  1888,  had  observed  the  pyrogenic  effect 
of  bacteria  and  noted  that  the  degree  of  temperature  rise  produced  by  the 
injection  of  bacteria  had  an  intimate  relation  to  the  state  of  digestion  of 
the  bacterial  cells.  Later  Charrin  and  Ruffer  noted  that  when  bacteria 
were  heated  to  a  temperature  of  110°  C.  they  still  retained  this  property 
of  causing  a  rise  in  the  temperature,  while  other  nonbacterial  proteins  also 
caused  an  increase  in  the  temperature  (bouillon  and  organ  extracts).  As 
a  matter  of  fact,  the  observation  that  such  substances  were  pyrogenic  was 
made  previously  by  Roux  and  Lepine.  Later  Buchner  worked  along  the 
same  line,  incidentally  observing  the  fact  that  on  reinjection  the  animal 
may  respond  differently  than  after  the  first  injection  (one  of  the  early 
observations  of  sensitization  and  anaphylaxis).  Ott  and  Collmar  had  tried 
out  a  variety  of  protein  split  products — albumoses,  peptone,  and  neurin — 
in  the  smaller  laboratory  animals,  but  had  obtained  very  irregular  pyro- 
genic effects.  Then  Krehl  and  Matthes  published  a  series  of  observations 
concerning  the  effect  of  bacterial  and  other  split  products  on  animals 
(normal,  and  sensitized  by  some  infection  such  as  tuberculosis),  the  results 
of  which  have  already  been  discussed.  Krehl  noticed  particularly  that  the 
experimental  animals  varied  in  their  sensitiveness  to  the  protein  split  prod- 
ucts. The  guinea  pig  was  most  susceptible  to  deuteroalbumose,  the  rabbit 
less  ^so  and  the  dog  least,  quite  the  same  relation  that  we  find  in  anaphy- 
lactic  shock. 

Schittenhelm  and  Weichardt  and  their  associates— Hartmann,  Greiss- 
hammer,  Strobel,  etc.— made  intensive  studies  of  the  temperature  curve, 
the  leukocytosis,  the  nitrogen  excretion  and  general  clinical  picture  fol- 


THEORIES  OF  MECHANISM  OF  REACTION  85 

lowing  protein  injections  of  various  kinds  in  a  variety  of  animals.  The 
leukocytic  picture  and  the  temperature  curves  have  been  discussed  under 
their  respective  sections.  They  noted  among  other  things  that  the  ex- 
cretion of  nitrogen  was  markedly  augmented  when  the  animal  was  sensi- 
tized and  then  injected,  or  when  a  very  toxic  protein  such  as  that  derived 
from  the  colon  or  typhoid  bacillus  was  injected.  The  derivatives  of 
nuclear  destruction  in  particular  were  found  to  be  increased.  While  the 
effect  on  the  temperature  might  be  relatively  negligible,  such  injections, 
particularly  in  dogs,  might  produce  a  change  in  the  leukocytic  picture 
lasting  at  least  a  day  and  an  increased  nitrogen  metabolism  that  would 
cover  a  period  of  4  days. 

In  dealing  with  protein  intoxication  Weichardt  and  Schittenhelm  em- 
phasize that  the  bacterial  bodies  contain  too  large  a  variety  of  proteins 
and  protein  split  products  to  obtain  a  clear  picture;  the  isolated  components 
had  to  be  studied  before  conclusions  could  be  drawn.  They  observed  that 
proteins  that  were  made  up  largely  of  monoamino-acids,  such  as  peptones 
derived  from  silk,  casein,  hair  or  edestin,  were  practically  not  toxic  to  the 
organism ;  on  the  other  hand,  the  diamino  rich  complexes,  such  as  histones 
and  protamins,  were  exceedingly  toxic.  According  to  Ruppel  these  are  pres- 
ent in  particularly  large  amounts  in  a  number  of  bacteria.  When  attached 
to  form  some  other  grouping,  as  for  instance  a  nucleohistone,  the  histone 
becomes  nontoxic.  Detoxication  can  therefore  take  place  in  the  direction 
of  synthesis  as  well  as  in  the  further  lysis  of  the  protein  complexes.  Of 
course,  even  on  lysis  toxic  amino-acids  may  be  formed,  as  when  beta-imid- 
azolylethylamin  is  formed  from  histidin.  (Studied  by  Barger  and  Dahl, 
Biedl  and  Kraus,  Schittenhelm  and  Weichardt.) 

From  their  further  studies  in  this  direction,  Schittenhelm  and  Wei- 
chardt concluded  that  the  conjugated  proteins  such  as  nucleoprotein,  hemo- 
globin, glutokyrin  sulphate,  etc.,  were  relatively  nontoxic,  whereas  the  pro- 
tein components  of  these  complexes  were  manifestly  toxic  (globin,  histone, 
protamin)  as  indicated  by  their  effect  on  the  blood  pressure,  temperature, 
respiration,  coagulability  of  the  blood  and  lethal  effect.  It  is  not  necessary 
to  add  that  this  toxicity  is  just  as  pronounced  when  the  derived  protein  is 
homologous  in  origin.  While  in  general  the  richness  in  the  diamino- 
acids  of  these  compounds  is  paralleled  by  their  toxicity,  this  is  not  the 
only  factor  involved. 

Of  exceeding  interest  is  their  work  with  hemoglobin,  which,  apart  from 
a  slight  temperature  effect,  was  practically  nontoxic.  They  were,  however, 
able  to  sensitize  animals  against  it.  On  the  other  hand,  globin  was  much 
more  toxic.  When  conjugated  with  hemochromogen  this  toxicity  again 
disappeared.  This  fact  is  of  particular  interest  in  several  pathological  con- 
ditions, such  as  malaria,  where  the  appearance  of  the  chill  and  the  high 
temperature  reaction  has  been  ascribed  to  the  liberation  of  hemoglobin 
and  its  derivatives.  Cowie  and  Calhoun  on  the  other  hand  are  inclined 
to  the  belief  that  it  is  due  to  protein  derived  from  the  plasmodia. 

Weichardt  and  Schittenhelm  made  the  further  observation  that  the 
continued  injection  of  the  proteins  that  caused  a  toxic  reaction  was  fol- 
lowed by  a  definite  cachexia  and  ultimately  by  death.  This  protein  cachexia 
seems  a  fairly  constant  phenomenon  and  has  been  observed  by  Bold  as 
well. 


86  PROTEIN  THERAPY 

Weichardt  then  proceeded  to  study  the  pharmacological  effects 
of  small  and  large  doses  of  the  various  higher  molecular  groupings 
of  the  split  products  of  proteins  on  individual  organs.  Small  doses 
were  found  to  stimulate  the  heart  muscles  as  well  as  the  hematopoietic 
system,  larger  doses  to  reduce  the  activity.  Similar  experiments  were 
made  on  the  activation  of  the  mammary  glands  of  goats.  A  series 
of  goats  secreting  equal  amounts  of  milk  were  injected  with  various 
amounts  of  protein  split  products  and  the  activation  of  the  metabolism, 
as  indicated  by  the  amount  of  milk  secreted,  could  be  studied  di- 
rectly. 

As  a  result  of  his  researches  and  clinical  experience  Weichardt 
has  come  to  the  conclusion  that  when  we  make  use  of  nonspecific 
therapy  we  stimulate  all  the  cells  of  the  organism  to  greater  activity 
in  the  production  of  either  specific  substances  antibacterial  in  char- 
acter or  merely  increase  the  general  resistance  to  intoxication  by  speed- 
ing up  the  mechanism  of  detoxication — either  synthetic  (the  forma- 
tion of  conjugate  proteins  from  the  toxic  forms)  or  lytic  (the  degrada- 
tion of  the  toxic  fragments  to  the  amino-acids)  or  in  some  other 
way  hastening  the  elimination  of  the  intoxicating  material. 

In  several  recent  papers  he  has  emphasized  a  number  of  points 
of  interest.  Thus  his  general  conception  that  nonspecific  therapy  is 
a  plasmaactivation — a  stimulation  of  the  cell  metabolism  and  func- 
tion, of  physiological  effort  rather  than  a  pharmacologic  alteration  in 
the  biological  processes  leads  to  a  correlation  with  the  problem  of 
fatigue,  to  which  he  has  devoted  a  considerable  study. 

Weichardt,  contrary  to  the  theory  of  Dollken,*  considers  this  stim- 
ulation or  activation  as  omnicellular.  The  leukocytosis,  the  increase 
of  oxidation,  of  catalysis,  the  mobilization  of  enzymes  and  antibodies 
all  indicate  a  general  rather  than  a  localized  stimulation  of  some 
particular  kind  of  tissue. 

This  stimulation  does  not  involve  any  alteration  in  function.  The 
organism  by  nonspecific  reaction  acquires  no  new  method  of  defense, 
probably  does  not  overcome  infection  or  intoxication  through  agencies 
other  than  those  always  at  its  disposal.  But  the  stimulation  repre- 
sents a  summation,  a  cumulative  effort  of  the  defensive  agencies  of 
all  the  organs.  And  as  a  necessary  corollary  it  is  but  logical  that  we 
can  achieve  no  therapeutic  effect  when  once  the  organs  have  by  com- 
plete exhaustion  been  rendered  incapable  of  reaction,  as  in  terminal 
stages  of  disease  processes  or  in  profound  intoxication,  etc. 

While  the  stimulation  does  not  involve  any  new  method  of  de- 

*  Dollken  considers  certain  proteins  and  other  agents  as  selective  in  charac- 
ter. Thus  milk  which  was  found  to  be  more  styptic  in  its  effects  than  vaccines 
or  albumoses,  he  considers  active  in  this  way  because  of  greater  stimulation  of 
the  liver— mobilization  of  fibrinogen  and  thrombokinase — deutero-albumose  being 
more  effective  in  mobilizing  antibodies,  etc.  It  seems  probable  that  while 
selective  differences  may  exist,  a  general  protoplasmic  stimulation  is  the 
phenomenon  which  must  primarily  be  considered. 


THEORIES  OF  MECHANISM  OF  REACTION  87 

fense,  differences  in  reaction  exist  between  normal  individuals  and 
individuals  ill,  or  sensitized.  The  cell  that  has  been  sensitized  re- 
sponds more  promptly  with  a  mobilization  of  protective  agents,  both 
specific  antibodies  as  well  as  enzymes  and  other  nonspecific  factors 
in  resistance. 

Inasmuch  as  the  subject  of  cell  stimulation  is  so  closely  bound 
up  with  cell  fatigue,  Weichardt  has  schematically  drawn  up  the  accom- 
panying classification  of  the  substances  and  agencies  that  are  opera- 
tive in  cell  stimulation  and  therefore  in  resistance.  (Page  88.) 

These  agents  fall  into  active  and  passive  groups;  the  passive  ones 
being  such  that  take  something — Weichardt  lays  particular  weight 
on  the  paralyzing  effect  of  fatigue  toxins — protein  split  products — 
from  the  cell.  They  are  identified  by  the  fact  that  their  activity 
becomes  manifest  only  when  symptoms  of  fatigue  have  become  evi- 
dent in  the  organ,  and  then  the  effect  can  never  bring  about  an  aug- 
mentation of  function  over  the  normal — a  mere  restitution  is  the  limit 
of  their  range.  Given  good  resorption  their  effect  becomes  apparent 
at  once,  while  in  high-grade  fatigue  they  fail  to  change  the  function 
to  any  degree. 

With  the  active  agents  we  deal  with  a  true  activation  whereby 
the  cells  are  excited  to  a  high  grade  of  activity,  demonstrable  not 
only  in  fatigued  but  in  nonfatigued  cells.  The  dosage  is  of  impor- 
tance as  Weichardt  showed  in  the  experiments  on  isolated  organs  and 
organ  systems.  The  dosage  must  be  proportional  to  the  organ  to  be 
stimulated  and  its  condition.  Usually  a  definite  latent  period  can  be 
determined  before  the  maximum  stimulation  becomes  manifest. 

Now  if  we  keep  in  mind  this  relation  of  stimulation  and  fatigue, 
that  small  amounts  of  split  products  (fatigue  toxins)  may  stimulate 
to  greater  activity  while  large  amounts  will  cause  only  depression, 
a  common  observation  of  nonspecific  therapy — namely  the  fact  that 
on  repeated  stimulation  by  intravenous  injections  the  organism  fails 
to  react — becomes  intelligible.  The  stimulation  wears  off,  in  severe 
fatigue  the  reaction  may  fail  entirely. 

Schittenhelm  in  his  recent  view  of  nonspecific  therapy  calls  at- 
tention to  the  fact  that  the  derivation  of  the  protein  split  product 
used  for  nonspecific  injections  cannot  be  indifferent  to  us.  Undoubted 
differences  must  exist  in  their  physiological  properties  of  stimulation 
or  depression.  There  is  no  doubt  that  chemically  defined  proteins 
would  be  best  and  some  work  has  already  been  done  in  this  direction. 
But  it  must  be  kept  in  mind  that  while  we  may  use  a  definite  protein 
complex  to  begin  with,  split  products  will  also  be  produced  during 
the  course  of  the  reaction  from  the  metabolites  of  the  body  and  will 
enter  into  the  reaction. 

The  euphoria  that  follows  the  nonspecific  protein  therapy  can  be 
observed  after  a  variety  of  similar  procedures,  both  chemical  and 
physical.  It  is  observed  after  the  injection  of  colloidal  metals  and 


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FIG.  3. — Classification  of  substances  and  agencies  operative  in  cell  stimulation 
and  resistance. 

88 


THEORIES  OF  MECHANISM  OF  REACTION  89 

Weichardt  calls  attention  to  the  fact  that  a  similar  state  is  to  be 
observed  after  the  use  of  faradic  current  (Bergonie).  Most  likely 
the  stimulation  of  the  lymphatic  flow  whereby  fatigue  products  are 
rapidly  removed  is  related  to  this  effect. 

Schittenhelm  and  Stroebel  a  number  of  years  ago  emphasized  the 
fact  that  under  normal  circumstances  protein  split  products  do  not 
get  into  the  circulation,  that  they  are  foreign  to  the  blood  and 
their  presence  would  be  manifest  at  once  in  an  intoxication.  Protein 
metabolism,  reconstruction  and  molecular  rearrangement  and  deg- 
radation take  place  within  the  cell.  In  this  cellular  metabolism 
the  protein  split  products  have  a  dual  effect.  In  small  amounts  they 
irritate  (stimulate)  the  cellular  activity.  In  larger  amounts  they 
are  depressants.  Weichardt's  "omnicellular  plasmaactivation"  means 
simply  that  we  make  use  of  the  same  agents-  in  proper  dosage  to 
stimulate  and  since  we  use  an  intravenous  route,  all  the  cells  of  the 
organism  are  stimulated  at  the  same  time. 

Selective  Stimulation. — Dollken  considers  that  differences  in  thera- 
peutic effect  exist  between  the  various  nonspecific  agents,  that  some  of  them 
stimulate  particular  organs  or  organ  groups  and  presents  a  number  of  obser- 
vations to  support  his  contention.  In  several  papers  he  has  pointed  out  dif- 
ferences in  effects  when  various  bacterial  injections  are  made — heterobac- 
teriotherapy — thus  pyocyaneus  vaccines  were  found  effective  in  gummas, 
pseudodiphtheria  vaccines  were  not ;  cholera  and  dysentery  vaccine  were  not 
effective  in  neuralgia,  while  vaccines  made  up  with  prodigiosus  organisms 
were  very  satisfactory.  On  the  other  hand  neither  prodigiosus  nor  pyo- 
cyaneus vaccines  gave  any  clinical  result  in  acne,  while  an  autogenous 
vaccine  did.  The  effects  could  therefore  not  be  considered  identical. 
When  comparing  the  styptic  effect  it  was  noted  that  the  bacterial  vaccines 
were  practically  without  effect  whereas  milk  was  very  active.  ...  It  was 
interesting  to  note,  too,  that  while  the  local  reaction  at  a  focus  might  be 
equal  for  two  different  substances,  the  end  results  might  be  wholly  differ- 
ent. Thus  both  prodigiosus  vaccine  and  milk  gave  equal  reactions  about 
arthritic  foci,  but  the  clinical  results  with  the  prodigiosus  vaccine  were  not 
good.  On  the  other  hand,  when  treating  neuritis  the  prodigiosus  vaccine 
gave  better  results  than  did  milk  injections. 

Dollken  is  of  the  impression  that  the  nonspecific  stimulation  is  not 
omnicellular  as  Weichardt  has  suggested  but  that  certain  organs  are  stimu- 
lated by  different  agents  to  a  greater  degree  than  others,  these  being  the 
liver,  spleen,  kidney  and  bone  marrow;  a  decided  effect  is  also  obtained 
on  joints,  the  tissues  of  the  eye  and  some  of  the  glands  and  paraglandular 
structures.  Dollken  has  made  the  interesting  observation  that  the  effect 
on  joints  is  not  merely  a  bactericidal  one,  as  might  be  inferred  when  an 
infectious  arthritis  is  improved,  but  even  joint  inflammations  such  as 
those  of  gout  are  also  relieved,  certainly  not  a  bacterial  affair. 

Dollken  noted  that  the  repeated  injections  of  heterovaccines,  milk  and 
similar  substances  resulted  in  different  reactions.  Thus  the  resistance  of 
the  body  increases  rapidly  to  further  injections  of  pseudodiphtheria  bacilli, 
to  typhoid  bacilli  and  to  the  bacillus  pyocyaneus;  the  resistance  to  tuber* 


90  PROTEIN  THERAPY 

culin  and  to  prodigiosus  vaccine  goes  up  much  more  slowly.  Repeated 
injections  of  milk  and  of  deuteroalbumose  give  rise  to  steadily  augmented 
temperature  reactions,  indicating  a  certain  degree  of  sensitization.  Then, 
too,  the  fact  that  following  the  injection  of  heterovaccines  the  euphoria 
so  commonly  present  after  the  other  agents  is  seldom  noted,  also  indicated 
some  difference. 

It  may  be  well  to  leave  the  question  whether  the  plasmaactiva- 
tion  is  omnicellular  or  organotropic  and  take  up  some  of  the  other  the- 
ories that  have  been  advanced  to  explain  the  nonspecific  reaction. 

Effect  on  Thermoregulatory  Mechanism. — Paltauf  suggests  that 
the  effect  might  be  due  to  thermogenic  substances  in  the  vaccine 
injected.  After  the  stimulation  of  the  heat-regulating  center  an  ex- 
haustion might  be  expected,  as  an  expression  of  which  he  regarded  the 
defervescence  after  nonspecific  injections  in  acute  febrile  diseases. 
This  explanation,  which  Lowy  supports,  does  not  take  into  considera- 
tion the  frequent  permanency  of  the  defervescence. 

Saxl  considered  the  hyperthermia  as  the  vital  factor  which  stimu- 
lated both  antibodies  and  leukocytes  and  was  also  directly  effective 
on  the  disease  process. 

Roily  and  Meltzer  have  studied  this  question.  In  animals  that  were 
infected  with  a  single  overwhelming  dose  of  some  infectious  agent,  the 
effect  of  raising  the  temperature  was  not  apparent  in  the  course  of  the 
disease  process ;  on  the  other  hand,  if  the  animals  were  infected  with  small 
repeated  doses  and  over  a  longer  period  of  time  it  became  apparent  that 
by  increasing  the  temperature  the  infectious  process  was  favorably  in- 
fluenced. The  opsonic  power  of  the  serum  of  the  fever  animals  was  in- 
creased over  that  of  the  controls;  the  bacteriolytic  property  was  not  en- 
hanced. There  seemed  no  difference  in  resistance  to  pure  toxins  but  Roily 
and  Meltzer  observed  that  the  agglutinin  production  by  the  heated  animals 
was  increased.  Animals  that  were  kept  at  a  high  temperature  for  a  period 
of  over  20  days  showed  no  parenchymatous  degeneration,  but  did  show 
a  loss  of  weight  and  were  anemic. 

Liidke  has  determined  that  high  temperatures  per  se  are  not  damaging 
factors  in  infections,  for  if  in  infectious  diseases  the  temperature  is  arti- 
ficially raised,  the  disease  is  seemingly  favorably  influenced.  Liidke  has 
noticed,  however,  that  on  artificially  increasing  the  temperature  we  may 
activate  latent  organisms.  He  has  observed  that  typhoid  bacilli  that  have 
(in  convalescence)  been  dormant  in  the  spleen  or  bone  marrow,  may  again 
enter  the  blood  stream  on  superheating  the  organism,  i.e.,  a  hyperpyrexia 
may  at  times  be  a  cause  of  relapse  in  typhoid  fever. 

Antibodies  that  had  gradually  disappeared  after  an  infectious  disease 
or  following  immunization  artificially  produced,  were  again  found  in  the 
serum  after  any  procedure  that  increased  the  body  temperature,  whether 
by  increasing  the  external  temperature,  influencing  the  thermal  center 
of  the  brain  or  by  injecting  pyrogenic  drugs.  Liidke  is  therefore  inclined 
to  the  opinion  that  the  therapeutic  effect  of  hot  baths  and  sweats  during 
the  course  of  any  infectious  process  could  be  accounted  for  on  this  basis 


THEORIES  OF  MECHANISM  OF  REACTION  91 

and  considered  the  use  of  antipyretic  substances  as  illogical,  apart  from 
the  direct  toxicity  that  they  might  possess. 

Uddgren,  as  a  result  of  extensive  study  with  milk  injections,  has  come 
to  the  conclusion  that  the  hyperthermia  is  not  responsible  for  the  clinical 
improvement.  Working  with  eye  diseases  she  found  that  with  "sterile" 
milk  the  reaction  of  the  patient  was  very  mild  but  the  clinical  results 
were  just  as  good  if  not  better  than  when  market  milk  was  used  which 
gave  a  severe  reaction. 

Weiss  has  applied  this  theory  in  the  treatment  of  gonorrheal  infections 
with  very  hot  baths.  The  gonococcus  is  very  susceptible  to  heat  so  that 
it  offers  a  suitable  field  for  trial.  He  has  used  baths  heated  to  42°  C.  In 
some  instances  favorable  results  have  been  reported ;  most  patients  are  not 
able,  however,  to  stand  the  treatment  (Scholz).  (Kapperer.) 

Nolf  's  Theory. — Nolf  assumes  that  the  mode  of  action  is  the  fol-' 
lowing:  "Peptone  is  an  easily  assimilable  antigen.  The  pathogenic 
microbes,  on  the  other  hand,  antigens,  are  difficult  of  assimilation.  A 
single  mechanism  brings  about  the  assimilation  of  both  when  they 
are  given  by  a  parenteral  route.  It  is  probable  that  the  administra- 
tion of  peptone  has  the  power  of  stimulating  this  mechanism  and 
of  thus  augmenting  the  destruction  of  the  microbes.  As  the  pro- 
teosotherapy  is  essentially  a  nonspecific  method,  it  can  with  advan- 
tage be  given  in  association  with  more  or  less  specific  chemical  sub- 
stances when  the  latter  alone  are  insufficient  for  bringing  about  the 
cure.  For  this  reason  I  have  used  proteosotherapy  in  conjunction 
with  hexamethylenamin  in  the  treatment  of  typhoid  fever,  and  with 
sodium  salicylate  in  daily  doses  of  6  gm.  in  the  treatment  of  septi- 
cemia  caused  by  streptococci  and  staphylococci  and  in  acute  arthritis." 

v.  Groer  believes  that  we  are  dealing  with  an  alteration  of  the 
entire  organism — "eine  Umstimmung"  or  a  desensitization,  largely  due 
to  the  loss  of  the  cell  receptors,  whereby  the  cell  becomes  less  liable 
to  intoxication.  This  view  will  be  discussed  more  fully  in  the  follow- 
ing chapter. 

Enzymes. — Holler,  Lindig,  Friedlander,  von  den  Velden  as  well 
as  Jobling  and  Petersen  have  emphasized  the  importance  of  the  proteo- 
lytic  enzymes  mobilized  after  the  injections.  Lindig  introduced  casein 
injections  on  this  basis  and  Jobling  and  Petersen  used  proteoses 
with  the  same  purpose  in  mind.  Lindig's  hypothesis  has  been  as 
follows:  The  serum  of  the  pregnant  woman  and  the  new-born  child 
contains  proteolytic  enzymes  which  digest  casein;  these  enzymes  are 
of  importance  in  preventing  infection.  Other  agents  may  stimulate 
enzyme  action,  such  as  colloidal  metals,  salt  solution,  etc.,  and  they 
have  been  successfully  used  in  therapy.  Lindig  considers  that  the 
enzymes  are  heterolytic  and  that  they  may  be  derived  either  from 
the  leukocytes  or  from  glands.  If  too  large  doses  of  proteins  are 
injected  an  excess  of  enzymes  floods  the  serum,  tissue-lysis  occurs  and 


92  PROTEIN  THERAPY 

the  protein  cachexia  to  which  Weichardt  has  called  attention  may 
result. 

Antibodies. — The  effect  of  the  nonspecific  injections  on  the  mobili- 
zation of  specific  antibodies  has  been  studied  by  a  number  of  ob- 
servers. Ludke  had  observed  that  proteose  injection  would  mobilize 
antibodies  in  immune  animals  and  introduced  proteose  injections  in 
patients  on  this  basis.  He  was  not  able  to  determine  a  constant  in- 
crease, however,  no  matter  what  the  clinical  result  of  the  injection. 
In  a  more  recent  paper  he  states  that  in  general  the  agglutinin  titer 
is  markedly  increased  in  the  typhoid  cases  that  he  had  injected, 
and  that  there  is  an  increase  in  the  bactericidal  property  of  the  serum. 
As  has  been  stated  in  a  previous  chapter  the  results  in  this  regard  are 
conflicting. 

Recently,  Larson  has  published  some  experimental  work  bearing 
on  this  point.  He  proceeded  on  the  theory  that  many  bacteria  such 
as  streptococci,  pneumococci,  etc.,  are  imperfect  antigens,  correspond- 
ing to  the  heated  tetanus  toxin,  the  toxoid;  that  during  a  streptococcus 
infection  such  as  an  acute  arthritis,  antibodies  are  formed  against  the 
streptococci,  but  as  this  organism  does  not  possess  the  second  stimu- 
lus— the  exfoliative  stimulus — that  is  necessary  to  cause  the  antibodies 
to  be  cast  off  into  the  blood  stream,  not  sufficient  immunity  is  estab- 
lished to  overcome  the  infection.  This  stimulus,  Larson  assumes,  is 
supplied  by  the  nonspecific  agent — the  vaccine,  foreign  serum,  pro- 
teose, etc.  In  other  words,  the  stimulus  necessary  to  cause  the  cells 
to  produce  the  antibodies  is  specific,  but  the  stimulus  causing  the 
cells  to  throw  off  the  antibodies  is  not  necessarily  specific.  Using 
rabbits  immunized  to  sheep's  corpuscles  Larson  found  that  the  in- 
jection of  foreign  proteins  greatly  augmented  the  antibody  content  of 
rabbits  that  had  only  a  very  low  antibody  content  before  the  in- 
jection. On  the  other  hand,  if  a  rabbit  had  originally  responded 
with  a  high  concentration  of  antibodies  the  secondary  injection  of 
a  foreign  protein  did  not  further  increase  the  antibodies  present  in 
the  serum. 

From  these  premises  Larson  draws  the  conclusion  that  the  in- 
jection of  foreign  protein  enables  the  organism  to  throw  off  the  so- 
called  sessile  antibodies  and  get  them  into  the  circulation.  In  view 
of  these  facts,  it  is  possible  that  the  various  agents  may  act  as 
stimulants  of  the  hematopoietic  tissue,  thus  suddenly  flooding  the 
body  with  immune  substances,  thereby  overcoming  the  infection. 
According  to  Wright,  vaccine  injections  were  supposed  to  be  followed 
by  a  negative  phase,  at  least  so  far  as  the  opsonic  power  was  con- 
cerned. Contrary  to  this  generally  accepted  view,  Bull  has  recently 
shown  that  this  does  not  hold  true  following  the  intravenous  injection 
of  a  typhoid  vaccine  in  immunized  rabbits.  Bull  noticed  that  the 
antibodies  were  not  diminished;  on  the  contrary,  they  were  rapidly 
increased  following  the  injection.  If  this  is  the  mechanism  involved, 


THEORIES  OF  MECHANISM  OF  REACTION  93 

it  is  important  to  bear  in  mind  that  the  stimulus  itself  is  not  a 
specific  factor,  but  that  the  hematopoietic  system  has  been  attuned 
to  respond  to  a  nonspecific  stimulus  with  the  production  of  a  spe- 
cific substance.  Larson  raises  a  question  in  this  connection  that 
has  occurred  to  many  in  the  treatment  of  pneumonia  (especially  of 
type  I)  where  some  observers  claim  to  have  obtained  results  with 
normal  horse  serum  equal  to  those  attained  with  the  specific  serum. 
That  is,  are  we  dealing  with  the  actual  amelioration  of  symptoms  be- 
cause of  the  antibodies  contained  in  and  injected  with  the  horse  serum, 
or  with  a  nonspecific  reaction  in  which  the  antibodies  that  bring  about 
the  cure  of  the  patient  are  derived  from  the  patient  under  the  stimulus 
of  the  injection?  The  fact  that  Type  I  serum  does  not  particularly 
influence  Type  II  pneumonia  would  speak  against  the  supposition 
raised  by  Larson. 

As  a  matter  of  fact  this  alteration  of  the  antibody  content  after 
the  injection  of  foreign  proteins  is  by  no  means  a  constant  affair  in 
clinical  studies  and  cannot  be  considered  the  sole  basis  of  the  thera- 
peutic result.  Thus  v.  Groer  found  no  increase  in  antibodies  after 
the  injections,  while  Rohonyi  found  not  only  that  the  antibodies,  in- 
cluding the  agglutinin  titer,  the  bactericidal  titer  and  the  opsonic 
index,  were  not  altered  but  were  at  times  actually  decreased  after 
the  therapeutic  injection  and  this  despite  the  fact  that  the  patient 
was  clinically  cured.  Rohonyi  made  the  further  interesting  observa- 
tion that  in  some  of  these  afebrile  typhoids  a  positive  blood  culture 
was  at  times  obtained  several  days  after  the  injection  and  after 
the  subsidence  of  the  clinical  symptoms.  This  finding  has  not  been 
confirmed.  (Decastello.) 

Wright's  Theory — Wright  believes  that  the  old  conception  that  vaccines 
are  contraindicated  in  acute  infections  because  it  would  be  like  adding 
poison  to  a  poisoned  system  does  not  apply  in  infections  because  immune 
responses  are  primarily  developed  in  the  infected  area  and  as  long  as  some 
portions  of  the  body  remain  which  are  not  involved,  these  uninvolved  por- 
tions may  be  activated  by  vaccine  inoculations  for  antibody  formation  to 
aid  the  involved  portions  as  a  reserve  force  in  overcoming  the  infection, 
and  that,  contrary  to  previous  conceptions,  it  is  found  that  antibodies  are 
rapidly  formed  when  vaccines  are  injected  into  healthy  tissues.  In  this 
connection  he  calls  attention  to  the  great  benefit  that  was  obtained  from 
vaccine  inoculations  especially  in  "Poisoned  wounds"  with  streptococcus 
cellulitis,  lymphangitis,  erysipelas,  etc.,  and  states  that  the  most  striking 
results  are  obtained  when  vaccines  are  employed  early  in  acute  cases. 

As  a  means  of  more  clearly  expressing  immunizing  processes,  he  pro- 
poses a  series  of  new  terms.  Terminology,  as  now  applied  in  immunology, 
has  a  pronounced  tendency  to  confuse  the  average  reader.  It  is  difficult 
for  him  to  keep  the  importance  of  such  words  like  antigen,  amboceptor, 
agglutinins,  precipitins,  lysins,  opsonins,  etc.,  in  their  proper  relations  to 
immunizing  processes  without  a  consequent  confusion  of  ideas.  He  has 
attempted  to  clear  up  this  matter  by  pointing  out  that  in  infectious  proc- 


94  PROTEIN  THERAPY 

esses  and  immunity  there  are  essentially  two  factors  at  work;  ferment  pro- 
duction by  the  infecting  organism  for  the  purpose  of  preparing  the  food 
on  which  it  lives,  with  the  incidental  destructive  influence  on  the  involved 
tissues;  and  tissue  produced  ferments  which  have  a  destructive  influence 
on  the  invading  organisms  and  their  poisonous  products.  The  application 
of  the  word  ferment  is  well  understood  and  by  pointing  out  that  infection 
is  sustained  and  immunization  established  by  ferment  action,  the  difficulty 
of  conveying  thought  through  the  use  of  new  words  is  avoided.  The  sub- 
stances known  as  agglutinins,  precipitins,  lysins,  opsonins,  etc.,  may  all 
be  regarded  on  this  basis  as  cell  produced  ferments  exerting  varying  de- 
structive influences  on  the  invading  organisms.  This  power  of  cells  to 
produce  germ  destroying  ferments  would  conform  to  what  Wright  calls 
phylactic  power.  Kataphylaxis  would  designate  a  condition  in  which 
cell  secreted  protective  ferments  are  freely  conveyed  to  the  infected  area; 
anti-kataphylaxis  would  indicate  the  reverse  condition  and  epiphylaxis 
applies  to  an  augmented  immunizing  activity  by  calling  into  operation 
some  reserve  immunizing  force.  Whether  these  newly  coined  words  will 
more  clearly  convey  a  fixed  comprehension  of  the  immunizing  process 
than  the  terms  heretofore  employed  remains  to  be  seen. 

In  the  application  of  vaccines  much  emphasis  is  laid  on  the  importance 
of  creating  conditions  by  which  the  immunizing  substances  are  conveyed 
to  the  infected  area;  contending  that  therapeutic  immunization  will  less 
frequently  fail  through  faulty  conveyance  to  the  infected  area  than  through 
inefficient  antibody  formation.  This  is  accomplished  by  efficient  drainage, 
removing  necrotic  tissue,  instilling  hypertonic  salt  solution,  irritating  ap- 
plications, hot  fomentations,  etc. 

Wright's  experimental  work  showing  that  the  bacillus  of  gas  gangrene 
and  tetanus  bacilli  will  not  grow  in  freshly  supplied  blood  serum  but  will 
grow  freely  where  the  serum  is  contaminated  with  streptococci  or  staphy- 
lococci,  while  streptococci  will  grow  in  unaltered  serum,  is  most  interesting 
and  shows  the  importance  of  removing  necrotic  tissues  and  inducing  a  free 
flow  of  blood  plasma  in  these  infections.  Since  streptococci  and  staphylo- 
cocci  grow  freely  in  blood  serum,  he  calls  these  organisms  serophites.  That 
these  organisms  are  destroyed  by  leukocytes  is  most  cleverly  demonstrated 
by  his  glass  lath  experiment.  Here  he  shows  that  when  the  leukocytes  are 
washed  with  serum,  bacterial  destruction  takes  place  by  phagocytosis, 
whereas  when  the  leukocytes  are  washed  with  normal  salt  solution,  the 
organisms  are  destroyed  by  the  mere  presence  of  the  leukocyte.  Where 
destruction  takes  place  by  phagocytic  action  it  is  clearly  accomplished  by 
a  digestive  process  and  where  bacteria  are  destroyed  or  inhibited  in  their 
growth  by  the  near  proximity  of  the  washed  leukocytes,  this  action  is 
necessarily  due  to  some  ferment  action  by  the  leukocyte.  That  bacteria 
destroying  properties  develop  when  killed  staphylococci  or  streptococci  are 
added  in  proper  numbers  to  normal  blood,  either  in  vitro  or  in  vivo,  is 
clearly  demonstrated  and  it  is  found  that  this  germ  destroying  power  ia 
both  specific  and  nonspecific.  This,  he  contends,  conforms  to  clinical  ex- 
perience and  furnishes  a  scientific  basis  for  obtaining  therapeutic  results 
from  vaccines  aside  from  their  specific  immunizing  action.  This  non- 
specific action  of  vaccines  also  explains  the  fact  that  often  better  results 
are  obtained  from  the  use  of  stock  vaccines  than  from  autogenous  prepa- 


THEORIES  OF  MECHANISM  OF  REACTION  95 

rations;  that  in  such  cases  the  patient  has  probably  come  very  near  to  the 
end  of  his  tether  in  immunizing  responses  to  the  existing  infection  when 
collateral  immunization  will  accomplish  the  desired  results.  This  he  con- 
siders very  important,  because  it  embraces  such  a  large  percentage  of 
cases  and  says: 

"We  are,  however,  here  considering  primarily  the  question  of  principles, 
and  in  connection  with  this  what  is  of  fundamental  importance  is,  that 
we  should  discard  the  confident  dogmatic  belief  that  immunization  must 
be  strictly  specific,  and  that  we  should  in  every  case  of  failure  endeavor 
to  make  our  immunization  more  and  more  strictly  specific.  We  should 
instead  proceed  on  the  principle  that  the  best  vaccine  to  employ  will  always 
be  the  vaccine  which  gives  on  trial  the  best  immunizing  response  against 
the  microbe  we  propose  to  combat. 

"I  would  point  out  that  this  would  almost  certainly  not  involve  any 
revolutionary  changes  in  the  accepted  practice  in  either  serum  therapy  or 
in  prophylactic  or  ordinary  therapeutic  inoculation.  But  it  would  mean 
taking  into  account  in  cases  which  proved  intractable  to  treatment  with 
the  homologous  vaccine  the  possibility  of  seeking  for  collateral  immuniza- 
tion by  inoculating  a  microbe  or  mixture  of  microbes  other  than  that  which 
the  patient  is  infected." 

Wright's  work  emphasizing  the  importance  of  the  tissue  enzymes 
in  local  resistance  to  bacterial  infection  is  of  interest,  although  we 
are  of  the  impression  that  the  terms  that  have  been  coined  by  him 
are  superfluous  and  will  merely  add  to  the  confusion  produced  by  an 
already  overburdened  nomenclature.  It  would  seem  much  more 
rational  to  determine  the  exact  role  of  enzymes  already  known 
and  for  which  we  possess  adequate  terms,  in  the  reactions  that  are 
involved  in  tissue  resistance;  only  when  we  have  exhausted  this  field 
would  it  seem  justified  to  bring  in  new  terms  to  cover  hypothetical 
factors.  The  antibody  reactions  should  not  be  confused  with  enzyme 
reactions,  no  matter  how  much  we  may  be  tempted  to  do  so. 

Ottenberg  and  Wallach,  who  have  repeated  some  of  Wright's  ex- 
periments on  the  production  of  nonspecific  bactericidal  substances  by 
methods  described  by  him,  failed  to  confirm  his  findings. 

Leukocytosis. — The  reactive  leukocytosis  that  follows  nonspecific 
injections  has  been  repeatedly  studied  and  the  suggestion  was  ad- 
vanced quite  early  that  the  therapeutic  effect  was  to  be  sought  in 
the  artificial  leukocytosis  established.  As  noted  elsewhere  this  leu- 
kocytosis which  follows  a  primary  leukopenia,  is  largely  polymorpho- 
nuclear  in  character;  occasionally  an  eosinophilia  has  been  described 
(Holler,  Rohonyi),  suggesting  some  relation  to  the  anaphy lactic  pic- 
ture. It  has,  however,  been  the  general  experience  that  the  therapeutic 
effect  need  not  parallel  the  leukocytosis  that  follows  the  injections: 
certain  cases  respond  very  favorably  as  far  as  clinical  results  are 
concerned  but  show  relatively  little  increase  in  the  white  count;  in 
other  cases  the  hyperleukocytosis  will  be  very  marked  but  the  thera- 
peutic effect  absent.  Gay  in  this  country  brought  out  the  role  of 


96  PROTEIN  THERAPY 

the  hyperleukocytosis  as  a  possible  factor  in  recovery  from  acute 
infections  and  considered  the  reaction  specific.  This  view  was  not 
upheld,  however,  by  later  workers — Zinsser,  McWilliams,  etc. 

Mueller  has  studied  the  leukocytic  response  in  considerable  detail 
and  calls  particular  attention  to  the  fact  that  myelocytes  and 
nucleated  red  cells  make  their  appearance  very  frequently  after  the 
nonspecific  injections,  indicating  a  very  profound  stimulation  of  the 
bone  marrow.  On  this  basis  he  has  recommended  and  used  milk  in- 
jections in  the  treatment  of  secondary  anemias.  Mueller's  results 
rather  support  the  contention  of  Dollken  that  nonspecific  injections 
do  not  necessarily  stimulate  the  entire  organism  but  may  be  se- 
lective, i.  e.,  acting  chiefly  on  the  liver,  bone  marrow,  etc. 

Starkenstein 's  Theory. — Perhaps  one  of  the  most  suggestive  and 
illuminating  researches  in  the  field  of  the  mechanism  of  nonspecific 
therapy  has  been  that  of  Starkenstein.  Starkenstein  would,  in  the  first 
place,  widen  the  concept  of  the  reaction  from  that  of  a  protein  therapy, 
or  a  heterotherapy  to  one  embracing  the  entire  collection  of  agents 
— a  true  nonspecific  therapy — including  not  only  the  bacterial  or  pro- 
tein substances  in  common  use,  but  the  metallic  colloids,  the  various 
drugs  that  have  been  developed  such  as  succinimid,  quinin,  arsenic, 
etc.,  and  even  purely  physical  methods,  von  Groer  has  covered  this 
in  using  the  term  "Ergotropie"  to  designate  this  form  of  therapy. 

Starkenstein  has  been  able  to  show  that  the  various  agents  under 
consideration  bring  about  such  a  change.  The  method  used  is  a 
relatively  simple  and  direct  one  and  consists  in  injecting  sodium 
fluorescin  into  dogs  and  watching  the  permeability  of  the  vessels  of 
the  eye  to  the  dye  under  normal  conditions  and  following  the  injec- 
tion of  the  various  nonspecific  agents.  In  a  similar  fashion  the  agents 
were  studied  in  their  effect  on  a  keratitis  produced  by  mustard  oil. 
The  definite  retarding  or  accelerating  action  of  the  drugs  on  inflamma- 
tion could  be  studied  in  this  way.  Finally  Starkenstein  deter- 
mined the  alteration  of  the  toxicity  of  strychnin  and  of  phenol  in 
dogs  that  were  injected  with  the  agents. 

Starkenstein  found  very  definite  alterations.  Using  the  dye  it  was 
found  that  distilled  water,  calcium  chlorid,  milk  and  salt  injections 
all  altered  the  permeability  of  the  vessels.  A  long  list  of  substances 
was  found  to  be  "entzundungshemmend"  (anti-inflammatory).  This 
included  the  following:  quinin,  ethereal  oils,  calcium  salts,  morphin, 
nicotin,  atophan,  salicylates,  antipyrin,  magnesium  sulphate,  adrena- 
lin, serum,  plasma,  gelatin,  silicic  acid,  starch,  methylene  blue,  salt, 
water,  fuchsin,  iodin. 

In  the  experiments  dealing  with  intoxication  Starkenstein  calls 
attention  to  a  fact  that  a  number  of  Italian  observers  had  pre- 
viously noted,  namely  the  antagonism  existing  between  toxic  sub- 
stances (Lusini,  Lo  Menaco,  Kleine,  Brunner). 


THEORIES  OF  MECHANISM  OF  REACTION  97 

A  sublethal  dose  of  the  one  poison  will  protect  to  a  degree  against 
a  toxic  dose  of  the  next  poison.  When  Starkenstein  tried  out  the 
toxicity  of  strychnin  in  normal  animals  and  animals  previously  in- 
jected with  atophan,  milk,  or  calcium  chlorid,  the  prepared  animals 
were  found  to  be  resistant  to  the  poison.  With  phenol  poisoning 
analogous  results  were  obtained  with  one  exception.  While  animals 
injected  previously  with  albumose,  atophan  and  calcium  chlorid  were 
more  resistant  to  phenol  intoxication,  the  animals  injected  with  milk 
were  less  so.  Starkenstein  is  inclined  to  the  interpretation  that  this 
paradoxical  result  is  due  to  the  fact  that  the  phenol  is  more  soluble 
in  the  lipoids  of  the  milk  and  that  this  lipotropic  property  brings 
about  a  more  prompt  distribution  and  the  greater  activity  of  the 
poison. 

Clinically  Starkenstein  noted  excellent  results  by  the  nonspe- 
cific treatment  of  herpes  zoster,  venereal  complications,  eye  and  ear 
diseases  and  erysipelas ;  in  these  cases  there  was  at  first  an  invariable 
increase  in  the  inflammatory  process  and  the  local  reaction  at  the  site 
of  the  lesion,  together  with  a  leukocytosis.  Scar  formation  was  ob- 
viously hastened.  Blood  sugar  was  also  found  to  be  augmented  after 
the  injections. 

As  a  result  of  these  studies  Starkenstein  concluded  that  the  nonspe- 
cific agents  have  a  definite  effect  on  the  permeability  of  the  vessels,  and 
therefore  on  inflammatory  processes;  that  the  irritability  of  the  ner- 
vous system,  both  sympathetic  and  central,  seems  diminished  and  that 
the  organism  as  a  result  of  these  demonstrable  changes  becomes  more 
resistant  to  such  poisons  as  strychnin  and  phenol.  It  is  of  course 
known  that  the  irritabilty  of  the  central  nervous  system  is  increased 
during  protein  sensitization  and  diminished  after  protein  shock,  ob- 
viously conditions  analogous  to  those  studied  by  Starkenstein. 

This  alteration  in  the  permeability  of  the  capillaries  and  con- 
sequent effect  on  inflammatory  foci  has  also  been  studied  by  Luithlen, 
by  Siegert  and  by  Schmidt  who  consider  it  of  importance  in  the  non- 
specific therapeutic  effect. 

Rohonyi  has  suggested  that  the  effect  of  the  nonspecific  injec- 
tions is  to  produce  a  neutralizing  substance  against  the  invading 
bacteria  and  antitoxin.  No  experimental  evidence  points  in  this 
direction. 

Pemberton  has  suggested  another  factor  that  may  be  involved, 
particularly  in  the  mechanism  of  recovery  from  arthritis  after  intra- 
venous injection  of  typhoid  vaccine.  He  calls  attention  to  the  im- 
provement that  occurs  in  arthritis  after  lowering  of  the  food  intake 
of  the  body,  when  the  body  draws  on  its  glycogen  store.  According 
to  his  studies  there  seems  some  relation  of  the  glycogen  metabolism 
and  the  pathological  alterations  of  arthritis.  During  the  reaction  that 
follows  intravenous  injections  there  is  every  reason  that  we  have  an 


98  PROTEIN  THERAPY 

increase  in  the  rate  at  which  glycogen  is  metabolized,  and  Pemberton 
believes  that  the  increased  catabolism  of  the  glycogen  as  well  as  the 
incidental  low  food  intake  that  occurs  for  the  day  following  the  in- 
jection may  have  some  relation  to  the  cure  of  the  disease,  although 
it  cannot  be  the  sole  factor  in  bringing  about  the  result. 


CHAPTER  VI 
THE  PROBABLE  MECHANISM  OF  THE  REACTION 

In  discussing  the  theories  proposed  to  explain  the  mechanism  of 
the  therapeutic  processes  which  we  are  calling  into  play  when  non- 
specific therapy  is  used,  it  will  be  well  for  the  moment  to  dismiss 
the  rigid  conception  of  antibody  immunity  that  has  been  built  up  on 
the  researches  of  Ehrlich  and  the  contemporary  French  and  English 
workers,  not  because  it  is  unimportant,  rather  because  of  the  com- 
plication that  it  introduces.  Antibody  immunity  is  a  vital  factor 
in  protection  against  infectious  disease  and  in  overcoming  actual 
bacterial  infection.  In  the  nonspecific  reaction  the  therapeutic  benefit, 
however,  seems  largely  independent  of  the  specific  antigen-antibody 
balance.  The  fact  that  we  do  not  discuss  the  antibody  theory  in 
this  connection  should  not  give  the  impression  that  it  is  to  be  ignored 
as  a  factor  of  defense  and  of  resistance. 

Intoxication  by  Protein  Split  Products. — Antibody  resistance  has 
been  studied  most  completely  in  connection  with  the  neutralization  of 
the  specific  soluble  toxins  that  are  secreted  by  certain  bacteria,  notably 
the  diphtheria  bacillus,  tetanus  bacillus,  etc.  But  we  are  beginning  to 
take  greater  cognizance  of  the  fact  that  in  dealing  with  bacterial  in- 
toxication we  have  to  do  with  other  and  less  clearly  defined  toxic  sub- 
stances, broadly  termed  endotoxins  to  designate  the  fact  that  they 
form  an  integral  part  of  the  bacterial  body.  Some  of  these  are  possibly 
native  proteins  to  which  the  infected  organism  can  become  sensitized, 
while  others  may  be  primarily  toxic  to  the  infected  organism  without 
previous  sensitization.  We  must  also  consider:  (a)  Preformed  protein 
split  products  which  are  toxic.  This  toxicity  may  be  due  to  particular 
molecular  grouping  as  the  native  protein  molecule  is  broken  up  in 
the  normal  metabolism  of  the  bacterial  cell  or  to  the  chemical  con- 
figuration of  the  fragments;  those  containing  the  benzol  ring  with 
its  various  addition  radicals  being  most  toxic  (Baehr  and  Pick), 
(b)  Protein  split  products  formed  as  the  bacterial  protein  is  frag- 
mented in  the  host — after  the  bacterial  cell  has  died,  i.e.,  not  neces- 
sarily preformed  in  the  bacterium,  (c)  Toxic  growth  products  derived 
from  the  bacterial  metabolism  and  excreted,  (d)  Toxic  metabolic 
products  derived  from  the  pathologic  cellular  metabolism  of  the  in- 
vaded organism  (Jobling  and  Petersen,  Zimmermann,  etc.).  In  all 
these  enumerated  sources  of  toxic  material  derived  either  from  the 

99 


100  PROTEIN  THERAPY 

bacterial  cell  and  its  metabolites  or  possibly  from  the  pathologically 
altered  activity  of  cells  of  the  invaded  body,  proteins  and  their 
split  products  are  the  chief  components  with  which  we  have  to  deal.* 
Schittenhelm  has  emphasized  the  general  conception  that  the  splitting 
of  proteins  (apart  from  the  gastro-intestinal  processes)  is  purely  an 
intracellular  phenomenon  and  that  whenever  we  have  to  do  with 
extracellular  proteolysis  we  deal  with  a  pathological  condition  with 
tremendous  inherent  possibilities  of  intoxication.  It  is  therefore  our 
chief  concern  to  investigate  and  review  our  present  knowledge  of 
protein  intoxication,  of  enzymatic  detoxication  of  the  poisonous  pro- 
teins, of  resistance  to  protein  intoxication  and  of  the  bearing  of  this 
knowledge  to  the  problem  of  nonspecificity. 

Detoxication. — It  is  apparent  that  the  fundamental  factor  in  over- 
coming bacterial  intoxication  (not  due  to  the  soluble  exotoxins)  lies  in 
the  ability  of  the  cells  or  fluids  of  the  invaded  organism  to  digest  the 
toxic  protein  fragments  (and  the  native  protein  to  which  the  organism 
may  have  become  sensitized)  to  the  lowest  degradation  product — that 
is,  to  the  nontoxic  stage,  and  in  this  way  overcome  the  deleterious 
effect.  This  detoxication  may  also  be  brought  about  by  the  formation 
of  addition  products,  by  polymerization  and  by  proteosynthesis  in  gen- 
eral. Enzyme  activity,  then,  no  matter  under  what  immunological 
term  we  wish  to  classify  the  particular  phase,  must  be  considered 
among  the  basic  phenomena  which  have  to  do  with  overcoming  bac- 
terial invasion  itself.  The  study  of  the  proteolytic  enzymes  and 
their  relation  to  pathological  conditions,  of  the  factors  that  accelerate 
and  the  factors  that  retard  enzyme  activity  should  lead  us  to  some 
final  field  wherein  by  controlling  enzyme  activity  we  may  be  able 
to  achieve  therapeutic  results. 

The  role  of  the  enzymes  in  pathological  conditions  has  until  very 
recent  years  been  a  relatively  neglected  field  of  study.  Enzymes, 
whatever  may  be  their  nature  or  their  composition,  must  have  formed 
the  basis  of  the  structure  upon  which  the  animal  organism  built  up 
it  system  of  immunity.  The  unicellular  organism  must  certainly 
endeavor  to  overcome  harmful  extracellular  forces  by  means  of  its 
ability  to  excrete  enzymes,  and  the  intracellular  enzymes,  too,  must 
be  called  into  play  when  some  parasite  invades  the  cell.  The  path- 
finding  work  of  Metchnikoff  was  based  on  this  idea.  Specific  im- 
munity must  have  been  a  much  later  development  of  this  primitive 
and  nonspecific  factor  of  resistance.  A  number  of  investigators  have 
at  various  times  sought  to  identify  the  specific  activity  of  anti- 
bodies, more  especially  the  activity  of  complement,  with  various 

*  While  this  view  of  the  subject  is  plausible  and  quite  generally  accepted 
we  must  by  no  means  ignore  the  fact  that  even  here  contradictory  evidence  has 
accumulated,  a  discussion  of  which  will  be  found  in  the  recent  papers  of  Zinsser 
and  of  Tiele.  These  observers  seek  to  find  the  source  of  the  intoxication  due  to 
the  "endotoxin"  producing  bacteria,  as  well  as  the  intoxication  in  anaphylaxis, 
in  certain  physical  alterations  of  the  serum,  as  yet  not  clearly  defined. 


THE  PROBABLE  MECHANISM  OF  THE  REACTION    101 

known  enzymes,  but  without  apparent  success.  The  most  recent  work 
that  has  aroused  the  interest  of  the  medical  profession  in  this  con- 
nection has  been  that  concerned  with  the  so-called  Abderhalden  re- 
action. 

Abderhalden  sought  to  show  that  whenever  a  specific  protein 
was  introduced  parenterally  into  the  blood  stream,  specific  enzymes 
were  mobilized  which  digested  the  protein  so  injected.  This  reaction 
of  the  enzyme  and  the  substrate  was  demonstrated  by  means  of  the 
dialysis  reaction.  Unfortunately  for  this  work  the  center  of  interest 
was  early  shifted  from  a  study  of  the  fundamental  phenomena  to  par- 
ticularistic and  technical  disputation  of  details  involved  in  the  clini- 
cal popularization  of  the  test.  Abderhalden  was  undoubtedly  preju- 
diced in  favor  of  the  idea  of  the  specificity  of  proteolytic  enzymes 
because  of  his  study  and  his  familiarity  with  the  beautiful  specificity 
displayed  by  the  enzymes  that  hydrolyze  the  carbohydates.  How- 
ever, when  one  considers  that  the  variety  of  carbohydrates  with  which 
the  organism  has  to  deal  is  relatively  limited  as  contrasted  with  the 
endless  combinations  possible  in  the  protein  molecule,  this  prejudice 
is  not  necessarily  logical.  Possibly  Abderhalden  was  influenced,  too, 
by  the  immunological  conception  of  specificity;  indeed  he  seems 
to  have  had  the  hope  that  just  this  problem  would  find  its  solution 
in  the  specific  proteases.  The  proof,  however,  that  the  Abderhalden 
reaction  itself  did  not  have  the  merit  of  strict  specificity  that  its 
originator  claimed  for  it  (Plaut,  Peiper,  Jobling  and  Petersen,  etc.), 
carried  with  it  the  tendency  of  checking  further  investigation  in 
this  field. 

In  this  country  a  number  of  workers  became  interested  in  enzyme 
activity  in  relation  to  pathological  conditions.  Among  these  may 
be  mentioned  Opie  and  his  associates  and  Jobling  and  his  coworkers. 
Their  papers  have  appeared  chiefly  in  the  Journal  of  Experimental 
Medicine  during  the  years  1910  to  1917. 

Buchner,  Matthes  and  Krehl,  Schmidt-Muhlheim,  Schittenhelm, 
Fano,  De  Waele,  Beidl  and  Kraus,  Weichardt,  Vaughan,  Friedberger, 
Pfeiffer  and  numerous  other  investigators  have  established  the  causal 
relation  between  intoxication  and  fever  and  the  protein  split  products. 
We  therefore  assume  that  with  bacterial  invasion  the  intoxication 
of  the  organism  is  due  very  largely  to  proteins  and  their  split  products 
derived  from  Ihe  bacteria.  We  must  also  deal  with  toxic  protein 
material  that  is  derived  from  the  pathological  tissues  of  the  patient 
and  perhaps  from  alterations  in  the  colloidal  state  of  the  blood  plasma 
that  take  place  under  certain  conditions.  For  the  moment  the  source 
of  the  proteins  need  not  concern  us. 

If  we  are  justified  in  ascribing  major  importance  to  the  protein 
derivatives,  we  are  assuredly  justified  in  studying  the  mechanism  of 
detoxication  which  must  primarily  involve  the  role  of  the  proteolytic 
ferments  that  will  break  down  the  toxic  complexes  to  nontoxic  forms. 


102  PROTEIN  THERAPY 

The  Serum  Enzymes. — In  the  blood  stream  several  proteolytic 
enzymes  are  known  to  occur.  These  include  the  leukoproteases :  (a) 
one  that  acts  in  a  slightly  alkaline  or  neutral  reaction  and  is  capable  of 
splitting  native  proteins  largely  to  the  proteose  stage;  (b)  one  that  acts 
in  a  reaction  slightly  acid,  with  a  digestive  range  similar  to  the  first; 
(c)  an  erepsin-like  enzyme  active  in  a  neutral  medium  and  freely  hy- 
drolyzing  proteins  from  the  intermediate  stages  (albumoses  and  pep- 
tones) to  the  amino  acid  forms.  These  enzymes  seem  to  be  derived 
from  disintegrating  but  not  from  living  polymorphonuclear  leukocytes 
and  fluctuations  in  the  peripheral  leukocyte  count  are  not  indicative  of 
the  relative  titer  of  the  enzyme  concentration.  (Hedin,  Jobling  and 
Petersen,  etc.) 

Apart  from  the  leukocytes  as  sources  of  proteolytic  enzymes  we 
must  consider  those  derived  from  the  gastro-intestinal  tract,  the  large 
abdominal  organs  and  from  areas  pathologically  altered,  either  by 
infection  or  by  trauma,  burns,  toxins,  etc.  These  enzymes  include  a 
tryptase  or  protease — a  polyvalent  trypsin-like  ferment  active  in  a 
neutral  or  slightly  alkaline  reaction.  In  the  human  this  enzyme  is 
normally  present  in  only  a  very  slight  amount,  but  under  certain 
conditions  (pneumonia,  leukemia)  may  be  markedly  increased.  In  cer- 
tain animals  one  can  also  increase  the  amount  by  moderate  stimulation 
of  the  liver  (by  Roentgen  irradiation,  etc.).  In  many  of  the  smaller 
laboratory  animals  these  enzymes  are  present  in  a  considerable 
amount  in  the  serum,  especially  in  those  that  have  no  leukoprotease 
present  in  the  leukocytes  (guinea  pigs,  rabbits,  etc.). 

Serum  ereptase  or  peptidase  is  an  enzyme  able  to  digest  partly 
hydrolyzed  proteins  to  the  animo  acid  stage.  It  is  normally  present 
in  human  serum  in  small  amount.  But  after  feeding  it  is  increased, 
probably  entering  the  blood  stream  from  the  gastro-intestinal  tract 
via  the  lymph  current.  It  can  also  be  augmented  by  stimulating  the 
gastro-intestinal  tract  by  means  of  short  Roentgen  ray  exposure.  In 
smaller  animals  this  enzyme  is  present  in  relatively  large  amounts. 

We  have  to  deal  in  general  with  two  types  of  proteolytic  enzymes, 

(a)  the  true  proteases  capable  of  digesting  the  native  proteins,  and 

(b)  the  erepsin-like  enzymes    (peptldases)    that  are  able  to  digest 
only  partly  hydrolyzed  proteins ;  both  active  in  neutral  or  at  the  most 
in  a  reaction  varying  from  the  neutral  to  only  a  slight  extent.    The 
enzymes  of  the  first  variety  are,  however,  not  active  under  normal 
conditions  in  the  blood  serum  because  their  activity  is  inhibited  or 
checked  by  the  antiferment  of  the  serum.    In  small  localized  areas  the 
amount  of  true  protease  liberated  by  disintegrating  leukocytes  or  by 
other  causes  may  be  sufficient  to  saturate  the  antiferment  and  in 
this  case  digestion  may  go  the  entire  stage  from  native  protein  to 
amino-acids.    As  a  general  rule  the  protease  derived  from  the  leu- 
kocytes, active  in  the  slightly  acid  reaction,  is  more  active  than  the 
alkaline  acting  protease  and  autolysis  therefore  goes  on  much  more 


THE  PROBABLE  MECHANISM  OF  THE  REACTION    103 

rapidly  when  the  hydroxyl-hydrogen  ion  balance  veers  to  the  acid 
side.  The  increasing  acidity  acts,  too,  in  hastening  autolysis  in  an- 
other way  in  that  the  antiferment  property  of  the  serum  is  diminished 
as  the  acidity  is  increased.  Both  factors  enter  into  the  speeding  up 
of  enzymatic  process  when  the  reaction  becomes  slightly  acid. 

These  proteolytic  enzymes  of  the  serum  must  not  be  confused 
with  serum  complement  or  alexin,  as  is  frequently  the  case  in  im- 
munological  literature.  In  the  antibody  lysis  of  bacteria  Jobling 
and  Petersen  showed  that  there  was  no  associated  proteolysis.  What- 
ever type  of  enzyme  activity  may  be  involved  in  bacteriolysis,  pri- 
marily it  is  not  associated  with  proteolytic  digestion.  The  evidence, 
uncertain  though  it  is,  rather  indicates  that  the  lipolytic  enzymes 
are  more  closely  concerned  in  this  type  of  reaction. 

Inasmuch  as  the  true  proteases  of  the  serum  are  present  only  in 
relatively  small  amounts  under  normal  conditions  and  are  active 
only  under  special  conditions  (the  decrease  of  the  inhibitory  factors) 
and  then  only  locally,  it  is  evident  that  the  ereptases  may  assume 
greater  interest. 

The  ereptase  is  potentially  a  detoxicating  agent.  Bearing  in  mind 
the  fact  that  the  toxic  proteins  are  proteins  that  are  already  par- 
tially hydrolyzed  or  conjugated  proteins  dissociated  from  their  non- 
protein  radical,  an  enzyme  that  will  attack  these  partially  hydro- 
lyzed proteins  (albumoses  [proteoses],  peptones,  etc.)  and  hydrolyze 
them  to  the  amino-acid  stage  must  necessarily  be  an  agent  of  de- 
toxication.  A  mobilization  of  this  enzyme  could  then  be  considered 
only  as  of  beneficial  significance,  never  as  a  factor  in  the  production 
of  an  intoxication,  although  the  enzyme  may  appear  accompanying 
intoxications.  A  spontaneous  increase  in  the  amount  of  this  en- 
zyme during  the  course  of  disease  should  therefore  be  coincident  with 
clinical  improvement,  and  conversely,  the  diminution  of  the  enzyme 
should  permit  the  accumulation  of  toxic  split  products  and  an  in- 
crease in  intoxication.  It  may  be  permissible  to  digress  for  a 
moment  in  order  to  study  this  condition  in  greater  detail  and  examine 
the  relations  as  they  are  presented  to  us  in  lobar  pneumonia. 

Pneumonia. — For  a  number  of  years  investigators  have  emphasized 
the  possibility  that  a  definite  relation  exists  between  the  inception  of 
the  crisis  and  the  activation  of  the  proteolytic  ferments  in  the  area  in- 
volved. Edsall  and  Pemberton  in  particular  advanced  this  idea  and 
endeavored  to  make  the  logical  clinical  application  of  hastening  auto- 
lysis  as  a  therapeutic  measure  in  cases  of  delayed  resolution.  Later 
Jobling  and  his  associates  studied  the  serum  ferment  and  antiferment 
during  the  course  of  lobar  pneumonia,  noting  that  just  preceding  the 
crisis  protease  was  demonstrable  in  the  serum  while  the  antiferment 
began  to  diminish  from  the  high  titer  prevalent  throughout  the  early 
part  of  the  disease.  The  work  of  Weiss  on  the  crisis  is  similar  in  char- 
acter and  sets  forth  analogous  conclusions.  Lord  and  Nye  have 


104  PROTEIN  THERAPY 

approached  the  same  problem  and  lay  stress  on  the  changes  that 
occur  in  the  hydrogen  ion  concentration  of  the  exudate  of  the  pneu- 
monic lung,  which,  on  being  increased,  makes  possible  a  suitable 
reaction  for  the  augmented  activity  of  the  proteolytic  enzymes.  Ab- 
derhalden  in  investigating  the  enzyme  activity  of  pneumonic  sputum 
before  and  after  the  crisis  was  not  able  to  determine  the  presence 
of  any  peptidase  before  the  crisis,  but  with  the  inception  of  the  crisis 
found  such  enzymes  present  in  large  amounts.  The  fundamental 
idea  underlying  the  studies  in  this  direction  has  been  that  apart 
from  the  intoxication  arising  directly  from  and  incident  to  the 
growth  of  the  pneumococcus,  toxic  split  products  were  absorbed  from 
the  exudate,  which  indeed  could  be  considered  a  mass  of  foreign  pro- 
tein undergoing  slow  digestion  before  the  crisis.  Active  autolysis 
once  under  way,  only  the  lower  and  nontoxic  split  products  would  be 
absorbed  and  the  environments  for  the  further  proliferation  of  the 
pneumococcus  would  become  unfavorable,  for,  as  Almaggia  has  shown, 
pneumococci  are  very  susceptible  to  products  of  autolysis.  In  this 
phenomenon  the  reaction  is  primarily  a  local  and  a  cellular  one,  in- 
volving the  liberation  of  sufficient  leukoprotease  from  the  disintegrat- 
ing leukocytes  and  the  gradual  alteration  in  the  reaction  of  the 
medium  so  that  the  inhibitory  factors — i.e.,  the  alkalinity  and  the 
excessive  amount  of  antiferment — are  overcome.  Of  the  varieties  of 
the  proteolytic  enzymes  entering  into  this  reaction,  Jobling  and  his 
associates  studied  in  particular  the  protease,  as  before  mentioned,  while 
Petersen  and  Short  studied  the  ereptase  titer. 

We  can  assume  that  this  latter  form  of  enzyme  activity  would 
be  of  favorable  import  in  the  process  inasmuch  as  it  could  lead 
only  to  detoxication  through  the  complete  destruction  of  toxic  pro- 
tein fragments.  The  first  two  charts  illustrate  common  clinical 
pictures  in  lobar  pneumonia,  the  one  recovering  by  lysis,  the  other 
terminating  fatally  on  the  ninth  day  of  the  disease. 

Case  No.  1.  White  man,  43  years  of  age,  entered  hospital  March  14, 
1917,  after  an  illness  of  36  hours.  Diagnosis:  Lobar  pneumonia  of  lower 
right  lobe;  course  uneventful,  recovery  by  lysis  by  the  tenth  day.  (See 
Fig.  4.) 

It  will  be  observed  that  the  ereptase  titer  (peptidase)  remained 
uniformly  low  during  the  first  three  days  when  examined,  then  in- 
creased to  approximately  3  times  the  former  titer  on  the  8th  day  of 
the  illness  and  then  again  diminished.  The  increase  coincides  with 
the  period  of  clinical  recovery.  The  antiferment  titer  shows  the  usual 
increase  early  in  the  disease  and  a  diminution  during  the  period  of 
lysis  that  is  frequently  observed. 

Case  No.  2.  Colored  man,  27  years  of  age,  entered  the  hospital  April 
18,  1917,  having  been  ill  for  two  days.  Diagnosis :  Lobar  pneumonia  of  the 
lower  left  lobe;  aortic  regurgitation.  On  the  third  day  there  were  evidences 


THE  PROBABLE  MECHANISM  OF  THE  REACTION    105 

of  the  involvement  of  the  right  lobe  as  well,  and  the  patient  became  pro- 
gressively worse,  death  taking  place  on  the  ninth  day  of  illness. 

It  will  be  noted  in  Figure  5  that  the  titer  of  the  ereptase  is 
in  this  case  the  reverse  of  the  previous  one,  a  decrease,  being  appar- 

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106 


PROTEIN  THERAPY 


ent  after  the  3rd  day  that  persisted  until  death.  The  antiferment 
during  this  time  progressively  increased.  This  reaction  curve  of  the 
enzymes  is  characteristic  for  fatal  pneumonias. 

The  case  illustrated  by  Figure  6  is  perhaps  the  most  interesting 
in  illustrating  the  relation  of  the  ereptase  titer  to  the  clinical  condition 
of  the  patient. 

TEMPERATURE  CUK7B 


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FIG.  5. — ^The  ereptase  titer  and  antiferment  in  pneumonia  terminating  in  death, 


THE  PROBABLE  MECHANISM  OF  THE  REACTION    107 

Case  No.  3.  White  man,  age  34  years,  entered  the  hospital  on  March 
5,  1917,  with  a  diagnosis  of  lobar  pneumonia  of  the  lower  right  lobe  of 
three  days'  standing.  The  course  of  the  disease  was  quite  protracted.  By 
the  4th  day  after  admission  the  temperature  had  declined  and  the  patient 


TEMPERATURE  CURVE 


FIG.  6.— The  relation  of  the  clinical  condition  during  pneumonia  to  the  serum 
ereptase  and  antiferment. 

was  clinically  improved  when  an  extension  to  the  middle  lobe  occurred. 
The  temperature  increased  for  several  days,  then  declined  to  the  8th  day. 
At  about  this  time  the  lower  left  lobe  became  involved,  which  entailed  an- 
other rise  in  temperature,  followed  by  a  period  of  partial  recovery  with  a 
long  period  of  violent  temperature  fluctuations  superseding.  A  month 
after  admission  the  patient  was  still  running  an  irregular  febrile  course 


108  PROTEIN  THERAPY 

although  greatly  improved  clinically.    At  this  time  a  final  blood  examina- 
tion was  made. 

We  have  in  Figure  6  shaded  the  portions  when  the  patient 
was  making  clinical  improvement  after  each  lobe  was  involved.  The 
evidences  of  clinical  improvement— pulse,  respiration,  subjective 
symptoms  and  physical  findings — coincided  with  typical  changes  in 
the  enzyme  concentration  of  the  serum  as  can  be  observed  from  the 
chart. 

An  increase  in  the  ereptase  titer  took  place  during  each  period  of 
improvement  studied  (the  time  blood  samples  were  drawn  is  indi- 
cated on  the  chart  by  X)  but  declined  when  the  clinical  condition 
was  unfavorable.  The  antiferment  on  the  other  hand  invariably 
tended  to  diminish  during  the  favorable  periods  and  to  increase  with 
the  increase  in  the  lung  involvement.  These  alterations  are  so  typical 
and  so  clear  cut  that  their  clinical  significance  cannot  well  be  ques- 
tioned, even  though  the  interpretation  of  the  changes  may  be  open 
to  discussion. 

In  the  pneumonia  that  terminates  by  crisis  or  by  lysis  an  in- 
crease in  the  ereptase  titer  was  invariably  observed  by  us  either 
preceding  or  accompanying  the  clinical  change.  In  cases  that  termi- 
nated unfavorably  such  an  increase  was  not  found,  the  titer  in  these 
cases  usually  remaining  below  that  observed  in  normal  individuals. 
The  antiferment  titer  of  course  does  not  directly  influence  the  activity 
of  the  ereptase,  nevertheless  as  the  patient  improves  the  antiferment 
diminishes.  The  entire  condition  is  one  therefore  that  favors  a  rapid 
digestion  of  proteins. 

Ferment-Antiferment  Balance. — When  we  now  come  back  to  our 
consideration  of  the  true  proteases  we  deal  with  a  reaction  which  is 
much  more  complex  in  its  character  and  its  possibilities  for  two  rea- 
sons: (a)  The  enzyme  action  may  involve  the  splitting  of  native  pro- 
teins to  the  higher  split  products.  If  this  concerns  a  nontoxic  native 
protein  to  which  the  body  is  not  sensitized  it  implies  that  a  new  toxic 
substance  is  produced  in  the  organism  itself.  If  on  the  other  hand  it 
involves  a  toxic  protein  or  one  to  which  the  organism  has  become  sen- 
sitized, then  the  enzyme  can  act,  too,  as  a  detoxicating  agent  when  it 
splits  the  protein,  (b)  The  ferment  action  is  balanced  by  an  anti- 
ferment  and  we  have  therefore  to  deal  with  two  variable  factors. 

For  purposes  of  illustration  the  pneumonic  condition  will  again 
serve.  Let  us  assume  that  the  pneumonic  focus  with  its  mass  of 
cellular  detritus  represents,  for  the  normal  tissue,  simply  so  much 
foreign  material  from  which  it  must  free  itself  by  digestion.  As  long 
as  digestion  proceeds  slowly,  higher  and  more  toxic  split  products 
will  be  absorbed  as  such;  digestion  proceeds  slowly  because  the  leu- 
kocytes are  still  living  (therefore  not  shedding  their  ferment),  be- 
cause of  the  alkalinity  of  the  reaction  of  the  exudate,  and  the  large 


THE  PROBABLE  MECHANISM  OF  THE  REACTION    109 

amount  of  antiferment  present  in  the  exudate  which,  of  course, 
inhibits  digestion.  If  now  the  antiferment  is  lowered,  either  because 
of  the  change  in  the  reaction  or  because  it  is  saturated  by  protease 
mobilized  from  some  other  organ,  while  at  the  same  time  protease 
and  ereptase  are  liberated  locally,  the  patient  will  be  detoxicated 
promptly  as  digestion  changes  from  a  state  of  inhibition  to  one  of 
acceleration.  In  this  case  the  liberation  of  the  true  protease  would 
be  associated  with  detoxication. 

Let  us  assume  on  the  other  hand  that  we  are  dealing  with  a 
quiescent  tubercle,  one  that  is  sufficiently  protected  by  a  connective 
tissue  encapsulation  to  prevent  the  absorption  of  toxic  material  from 
the  focus  that  has  been  walled  off.  If  for  any  reason  the  identical 
serum  reaction  or  local  reaction  that  has  been  hypothecated  above 
should  occur  in  such  a  patient  quite  the  opposite  clinical  effect  would 
ensue.  The  liberation  of  protease  would,  along  with  the  reduction 
of  the  antiferment  (protective)  titer,  promptly  begin  to  digest  away 
the  connective  tissue  of  the  capsule  and  allow  some  of  the  toxic 
material  from  the  focus  and  the  native  proteins  of  the  focus  as  well, 
to  escape  into  the  general  circulation  with  a  resulting  intoxication  of 
the  patient  and  activation  of  the  focus.  Fluctuation  of  the  protease 
titer  can  therefore  be  assumed  to  influence  pathological  processes  in 
a  fundamental  way  and  at  times  with  diametrically  opposite  clinical 
results.  But  this  fluctuation  of  the  protease  is  under  the  control 
to  a  certain  extent  of  the  antiferment  or  inhibitory  substance,  which 
thereby  becomes  an  integral  part  of  the  balance  which  we  have 
under  consideration.  Here  we  leave  the  enzymes  and  have  to  deal 
very  probably  with  lipoid  substances.  The  antiferment  is  not  an 
antibody  in  the  immunological  sense,  although  it  was  early  so  con- 
sidered; it  consists  of  the  highly  dispersed  unsaturated  lipoids  of 
the  serum  and  of  the  lymph  and  the  tissues.*  Its  titer  varies  there- 
fore with  at  least  three  conditions:  (1)  the  amount  of  the  lipoids 
present,  (2)  the  dispersion  of  the  lipoids,  (3)  and  the  chemical  struc- 
ture, that  is,  the  degree  of  unsaturation.  All  these  conditions  are 
subject  to  considerable  variation  and  any  of  them  may  cause  a 
change  in  the  titer. 

Thus  changing  of  the  dispersion  by  acidifying,  by  salting  and 
by  heating  to  a  sufficient  degree  inactivate  the  antiferment,  physical 
adsorption  by  certain  chemically  inert  adsorbing  surfaces  such  as 
fuller's  earth,  barium  sulphate,  agar,  etc.,  lowers  the  titer;  solution 
of  the  lipoids  by  chloroform,  ether,  acteone,  and  certain  of  the  alco- 
hols removes  the  antiferment  from  the  serum.  The  soaps  of  the 
unsaturated  fatty  acids  are  perhaps  the  most  comparable  substances 
which  are  available  and  with  them  one  can  simulate  many  of  the 

*  The  evidence  concerning  the  nature  of  the  antiferment  is  conflicting.  Bach 
and  Teal®  were  not  able  to  coafirm  the  results  of  Jobling  and  Petersen.  The 
papers  of  Tachigara,  Fujimoto,  etc.,  should  be  consulted. 


110  PROTEIN  THERAPY 

reactions  that  can  be  obtained  with  the  serum  antiferment.  There  is 
much  evidence  that  the  antiferment  lipoids  are  in  more  or  less  close 
physical  combination  with  the  serum  albumin.  With  this  fraction 
they  are  thrown  out  of  solution  with  the  usual  methods  of  separating 
the  serum  proteins. 

Clinically  it  is  known  that  the  antiferment  is  augmented  during 
a  number  of  conditions,  notably  in  the  acute  infections,  in  pregnancy, 
in  carcinoma  and  cachectic  states  in  general;  following  anaphylactic 
and  other  shock  reactions,  including  therapeutic  vaccination,  and  in 
certain  pathologic  processes  of  the  central  nervous  system  char- 
acterized by  degenerative  changes.  In  other  words,  the  increase  in 
antiferment  is  part  and  parcel  of  a  general  reaction  phenomenon 
of  the  body.  This  increase  seems  purposeful  in  that  an  increase  in 
the  antiferment  titer  would  tend  to  counteract  the  negative  nitrogen 
balance  incident  to  the  heightened  destruction  of  proteins  of  the  body 
commonly  observed  in  toxic  conditions. 

This  relation  of  the  antiferment  to  the  rate  of  protein  metabolism 
has  been  worked  out  in  rabbits  and  dogs  during  inanition  by  Jobling 
and  Petersen.  They  found  that  the  execretion  of  nitrogen  in  the 
starving  animal  was  in  inverse  proportion  to  the  amount  of  antifer- 
ment in  the  serum,  as  will  be  apparent  from  the  following  table: 


Animal  %  Inhibition  Nitrogen  Excreted 

No.  (Average  for  5  Days)  (Total  for  5  Days) 

1  41%  4.24  gms. 

2  66%  2.95  gms. 

3  71%  1.97  gms. 

4  73%  1.99  gms. 

This  holds  true  evidently  for  the  human,  although  it  has  not  yet 
been  fully  worked  out  in  normal  individuals.  Wilson,  for  instance, 
noted  the  increased  storage  of  nitrogen  during  pregnancy,  a  condi- 
tion associated  with  a  well-marked  increase  in  the  antiferment  titer. 
After  vaccine  shock  or  protein  shock  we  often  find  the  same  increase 
in  weight  during  the  time  when  the  antiferment  titer  is  increased. 
Thus  Holler  injected  himself  over  a  period  of  two  weeks  with  daily 
intravenous  doses  of  1  c.c.  of  deuteroalbumose  solution  (10%) ;  there 
was  no  clinical  reaction  corresponding  to  that  observed  in  patients 
ill  from  any  disease.  The  chill,  sweating  and  temperature  were  all 
absent  but  he  gained  in  weight  during  the  course  of  the  injections. 
This  has  been  the  general  experience  of  the  clinic  as  well  as  the  labora- 
tory. 

If  we  keep  these  simple  enzyme  balances  in  mind,  many  of  the 
changes  which  are  encountered  following  nonspecific  therapeutic  in- 
jections will  appear  quite  simple  and  logical.  One  balance  consists 
of  (a)  the  true  proteases  capable  of  splitting  native  proteins  all  the 


THE  PROBABLE  MECHANISM  OF  THE  REACTION    111 

way  to  their  lowest  split  products.  These  can  act,  therefore,  either 
as  (1)  intoxicating  agents  when  splitting  nontoxic  native  pro- 
teins to  the  toxic  stage,  (2)  or  as  detoxicating  agents  when  free  to 
split  the  partial  products  of  digestion  to  the  nontoxic  forms  or  when 
splitting  a  native  protein  to  which  the  body  has  become  sensitized. 
These  enzymes  are  counterbalanced  by  (b)  the  antiferment  of  the 
serum,  a  variable  factor.  The  ereptase  (c)  or  peptolytic  enzyme, 
capable  of  splitting  only  the  partly  hydrolyzed  proteins  (toxic)  to 
the  amino  acid  stage  (nontoxic)  and  therefore  to  be  regarded  as  a 
detoxicating  agent,  not  counterbalanced  by  an  antienzyme  and  there- 
fore free  to  act  whenever  present  in  the  serum  and  the  tissues. 

This  conception  of  a  balance  of  variable  factors  which  at  one  time 
may  act  in  a  detoxicating  manner,  and  in  other  cases  may  intensify 
a  disease  process,  has  been  discussed  fully  in  several  papers  and  we 
need  go  no  further  into  the  details  at  this  time.  (Jobling  and  Pe- 
tersen,  Jobling,  Eggstein  and  Petersen,  and  Petersen.) 

Nonspecific  Injections  in  Carcinoma. — Von  den  Velden,  who  was 
one  of  the  very  first  to  use  nonspecific  methods  in  the  treatment  of 
disease  (1906),  early  expressed  the  hypothesis  of  enzyme  action  as  the 
basis  of  the  therapeutic  results  and  has  maintained  this  ever  since.  He 
began  his  work  using  small  subcutaneous  doses  of  serum  albumin  and 
ovalbumin  in  5  and  10%  solution.  From  these  he  passed  to  the  use  of 
convalescent  serum,  tetanus  antitoxin,  normal  horse  serum,  and  finally 
to  the  use  of  milk  injected  intramuscularly.  In  treating  several  cases  of 
inoperable  carcinomata  he  observed  that  following  the  injection  the  pa- 
tient reacted  with  a  period  of  malaise  and  of  fever  for  a  period  of 
several  days  and  then  for  a  time  the  general  condition  of  the  patient 
improved.  There  were  a  gain  in  weight,  a  better  appetite,  lessened 
pain,  etc.  Under  the  treatment  the  tumor  would,  at  times,  show  de- 
cided regressive  changes.  With  tuberculin  injections  Dabney  ob- 
served a  similar  effect. 

This  experience  of  von  den  Velden  is  cited  in  this  connection 
merely  because  it  is  typical  of  the  result  achieved  by  all  the  non- 
specific agents  in  the  treatment  of  carcinomata  and  other  malignant 
diseases.  Beard  got  the  same  result  when  he  injected  trypsin;  Coley's 
fluid  and  tumor  autoly sates  give  a  similar  reaction;  colloidal  metals 
give  it.  The  mechanism  is  the  same  in  all  cases,  the  clinical  picture 
is  identical,  the  results  are  similar,  i.e.,  there  are  evidences  of  a 
decided  focal  reaction,  even  of  tumor  regression  in  size,  but  the 
actual  proliferation  of  the  neoplasm  is  not  checked  because  the 
vascularized  portions  of  the  tumor  are  in  nowise  interfered  with, 
the  regression  being  due  to  an  increase  in  the  necrosis  of  the  cen- 
tral and  less  vascularized  portion  of  the  neoplasm. 

Let  us  assume  that  an  injection  of  milk  has  been  made  intra- 
muscularly in  such  a  carcinoma  case.  The  temperature  heretofore 
has  been  practically  normal.  Several  hours  after  the  injection  there 


112  PROTEIN  THERAPY 

may  be  a  chill,  the  temperature  rises  sharply  and  instead  of  dropping 
after  a  few  hours,  as  it  would  in  an  ordinary  infectious  case,  stays 
high  for  from  24  to  48  hours.  Usually  this  reaction  is  accompanied 
by  general  malaise  and  every  indication  of  increased  inflammatory 
reaction  about  the  tumor.  After  this  period  the  temperature  drops, 
the  patient  feels  better  than  before  the  injection,  gains  in  weight, 
pain  is  lessened  and  retrogressive  changes  are  noted  in  the 
tumor.  It  has  been  shown  that  following  such  an  injection  of 
a  nonspecific  agent  a  definite  shifting  of  the  ferment-antiferment 
balance  takes  place  so  that  the  antiferment  is  lessened  and  the 
activity  of  the  protease  increased.  At  the  tumor  site  this  means  that 
this  protease  begins  to  digest  some  of  the  native  proteins  of  the 
necrotic  debris.  Toxic  split  products  are  liberated,  they  diffuse 
out  from  the  focus  into  the  surrounding  healthy  tissue,  cause  irri- 
tation, the  attraction  of  leukocytes,  vascular  engorgement,  increased 
tension  and  with  it  increased  pain.  It  is  during  this  period  of 
absorption  of  the  soluble  split  products  that  the  febrile  period  and 
systemic  effect  of  a  general  malaise  are  observed.  The  leukocytes 
attracted  by  the  digestive  inflammatory  reaction  partly  succumb, 
partly  migrate  from  the  field.  A  certain  amount  of  leukoprotease  is 
certainly  liberated  from  them.  During  this  period,  too,  we  have  an 
increase  in  the  amount  of  nitrogen  excreted — i.e.,  a  negative  balance. 
Then  follows  the  period  of  recovery  of  the  balance  and  the  change 
to  the  reparative  side.  The  antiferment  is  increased  over  the  amount 
present  before  the  injection;  the  protease  action  is  checked,  in- 
creased amounts  of  ereptase  make  their  appearance  and  detoxicate 
whatever  remnants  of  split  products  still  remain  near  the  focus. 
During  this  period  the  patient  manifests  every  sign  of  clinical  im- 
provement— euphoria,  increase  of  weight,  appetite,  etc.  The  in- 
crease of  weight  that  follows  the  increase  in  the  antiferment  curve 
has  been  worked  out  in  a  series  of  clinical  conditions  by  Breed. 

The  tumor  in  the  meantime  may  have  actually  decreased  in  size 
by  the  effects  of  the  reaction  because  a  certain  amount  of  necrotic 
material  has  been  digested  away.  It  is  of  course  evident  that  the 
living  tumor  cells  need  in  no  way  be  susceptible  to  the  effect  of  the 
enzymes  and  that  the  reaction,  as  far  as  a  matter  of  cure  is  con- 
cerned, is  not  to  be  regarded  as  a  therapeutic  agent  for  such  malig- 
nant conditions.  It  may  have  a  place  in  the  therapy  of  malignant 
conditions  if  by  producing  an  inflammatory  reaction  repeatedly  we 
can,  either  by  cellular  or  vascular  changes,  aid  in  the  resistance  of 
the  body  to  the  neoplastic  invasion  (Theilhaber) .  Until  we  have 
certain  knowledge  of  these  factors  in  tumor  growth  we  must  un- 
fortunately deal  more  or  less  empirically  with  the  conditions.  Nor 
must  it  be  forgotten  that  the  inflammatory  reaction  that  is  brought 
about  may  at  times  not  be  helpful  but  may  actually  stimulate  the 
tumor  cells  to  greater  activity  and  malignancy,  and  therefore  be  of 


THE  PROBABLE  MECHANISM  OF  THE  REACTION   113 

decided  harm  to  the  patient.  If,  however,  it  is  clearly  kept  in  mind 
that  only  clinical  improvement  and  amelioration  is  sought  and  the 
measures  used  in  this  sense,  then  it  may  have  a  place  in  our  legiti- 
mate methods  of  treatment  in  inoperable  cases. 

This  reaction  and  its  effects  on  the  local  condition  as  detailed 
here  is  quite  similar  to  that  which  has  been  studied  in  regard  to 
the  tuberculous  focus  and  is  more  fully  entered  into  elsewhere. 

The  Reaction  in  Local  Inflammation. — It  is  of  paramount  impor- 
tance for  the  purpose  of  studying  the  role  of  the  enzymes  in  this  non- 
specific reaction  to  keep  in  mind  the  fact  already  emphasized  in  the 
introduction  that  the  reaction  of  the  body  to  injury,  whether  chemical 
or  physical  or  bacterial,  is,  within  certain  limits,  always  the  same.  In- 
flammation, no  matter  how  produced,  is  fundamentally  alike  in  char- 
acter and  in  its  results. 

If  we  view  recovery  from  this  point  of  view  it  is  instantly  ap- 
parent that  nonspecific  therapy  offers  something  more  substantial  than 
an  evanescent  therapeutic  fad  or  a  bizarre  fancy  of  the  day  in  medi- 
cine. It  is  rather  a  procedure  that  has  as  the  foundation  of  its 
mechanism  biologic  processes  at  once  the  most  primitive  and  the 
most  universal  of  all  those  over  which  the  organism  disposes  in  its 
measures  of  defense  and  resistance  to  trauma  and  disease. 

If  it  can  actually  be  demonstrated  that  inflammation  is  altered 
by  nonspecific  reactions  we  can  conceive  that  the  hastening  of  the 
process  will  be  evidenced  in  two  ways:  in  one,  that  a  beginning  in- 
flammatory process  will  subside  without  suppuration,  in  the  other,  that 
an  advanced  or  rapidly  advancing  inflammatory  process  will  undergo 
softening  and  resolution.  As  a  matter  of  fact  these  are  precisely 
the  reactions  that  do  take  place  when  we  treat  local  inflammatory 
processes  by  nonspecific  means,  the  venereal  bubo  being  a  condition 
of  this  type  that  has  been  extensively  studied.  (Odstreil,  Miiller, 
Schneller,  Antoni,  etc.) 

When  a  bubo  is  treated  by  the  intragluteal  injection  of  milk 
one  can  observe  a  definite  focal  reaction  which  reaches  its  maximum 
in  from  six  to  eight  hours  with  an  increase  of  pain,  local  tenderness 
and  hyperemia.  Following  this  a  period  of  analgesia  sets  in.  If 
such  a  bubo  is  taken  under  treatment  early,  suppuration  never  takes 
place,  the  process  subsiding  without  it. 

If  the  local  inflammation,  on  the  other  hand,  is  further  advanced 
when  treatment  is  commenced,  softening  occurs  soon  after  the  in- 
jection, but  if  further  injections  are  then  made  no  incision  or  drain- 
age is  necessary,  according  to  Miiller,  because  the  necrotic  and 
softened  material  is  rapidly  absorbed.  In  only  one  out  of  25  cases 
did  Miiller  find  it  necessary  to  drain  the  bubo. 

This  effect  on  local  inflammatory  processes,  which  has  been  dis- 
cussed at  greater  length  in  the  chapter  on  The  Focal  Reaction,  can  be 
demonstrated  after  nonspecific  injections  wherever  the  lesion  is  so 


114  PROTEIN  THERAPY 

located  that  it  can  be  observed  directly,  as  in  the  skin  or  mucous  mem- 
branes. In  the  deeper  tissue  it  is  made  clinically  evident  by  the 
invariable  symptomatology  that  follows  the  injections — first  an  in- 
crease in  the  evidence  of  pain  and  temperature,  later  a  complete 
subsidence,  either  transient  or  permanent  as  the  case  may  be. 

We  believe  that  the  explanation  for  these  phenomena  is  relatively 
a  simple  one,  although  it  involves  at  some  time  practically  all  of  the 
tissues  and  structures  about  the  focus  of  inflammation,  changes  in 
both  the  blood  and  lymph  vessels  and  nerves,  as  well  as  in  the  local 
tissues  directly  involved. 

With  the  injection  there  is  first  apparent  an  increased  excitability 
of  the  central  nervous  system  and  the  sympathetic  system;  later  this 
subsides  and  ends  in  a  period  of  lowered  excitability.  There  is  at 
first  apparently  a  direct  effect  on  the  capillaries  so  that  they  become 
more  permeable — the  lymph  flow  is  increased,  the  tension  of  the 
local  inflammatory  focus  is  greater — the  pain  augmented.  Later  the 
reverse  sets  in  and  the  capillaries  become  less  permeable. 

But  in  the  meantime  certain  alterations  have  occurred  in  and 
about  the  focus.  We  may  assume  for  the  purposes  of  illustration  that 
we  are  dealing  with  this  early  bubo — a  certain  amount  of  toxic  ma- 
terial (protein  split  products  from  the  necrotic  tissue  of  the  venereal 
focus,  bacterial  endotoxins,  perhaps  soluble  toxic  materials  from  bac- 
teria, perhaps  a  few  bacteria  themselves  have  filtered  in  along  the 
lymph  channels)  has  been  brought  to  the  gland  and  has  incited 
an  inflammatory  reaction.  This  finds  its  expression  in  the  hyperplasia 
of  the  endothelial  cells  of  the  lymph  channels,  in  an  attraction  of 
polymorphonuclear  leukocytes  and  the  exudation  of  fluids  into  the 
tissues.  As  yet  there  has  been  no  necrosis. 

The  tissue  fluids  bathing  these  cells  contain  little  protease  or 
ereptase  but  much  antiprotease  (antitrypsin)  so  that  digestive  proc- 
esses are  held  in  abeyance.  Under  ordinary  conditions  the  intensity 
of  the  intoxication  is  therefore  not  diminished  and  tissue  necrosis 
finally  results,  both  the  fixed  cells  and  some  of  the  polymorphonuclear 
leukocytes  being  affected.  From  the  latter  we  now  have  the  libera- 
tion of  a  considerable  amount  of  protease,  sufficient  to  saturate  and 
thereby  negate  the  effect  of  the  antiferment  in  a  circumscribed  area 
— digestion  begins  to  take  place — solution  of  tissue  and  fluctuation. 

If  on  the  other  hand  at  an  early  stage  the  patient  is  given  a 
nonspecific  injection  the  focus  is  very  promptly  flooded — the  lymph 
flow  as  measured  in  the  thoracic  duct  is  increased  fourfold — and  in 
the  fluids  now  exuded  (the  permeability  of  the  capillaries  being  in- 
creased by  the  nonspecific  injection)  there  is  carried  considerably 
more  protease  as  well  as  ereptase,  while  the  antiferment  is  diminished. 
The  toxins  present  are  not  only  diluted  but  their  digestion  is  com- 
menced by  the  enzymes.  Necrosis  is  prevented  by  this  effect  on 
the  toxins.  The  capillaries  now  become  less  permeable,  the  fluids 


THE  PROBABLE  MECHANISM  OF  THE  REACTION    115 

are  diminished,  tension  and  pain  lessened  and  restitution  to  the  nor- 
mal takes  place. 

On  the  other  hand  we  may  suppose  that  the  process  had  already 
proceeded  to  the  stage  of  actual  destruction  of  some  cellular  ele- 
ments. We  bring  about  the  nonspecific  reaction  at  this  period.  Here 
the  flooding  of  the  area  with  exudate,  the  lowering  of  the  antifer- 
ment,  the  increase  in  the  proteolytic  enzymes  will  of  course  accelerate 
the  autolytic  processes  already  commenced.  But  this  digestion  will 
coincidently  tend  to  diminish  the  acute  toxic  effect  of  the  split  products 
and  other  toxic  protein  material  that  originally  caused  the  inflamma- 
tion; solution  of  the  necrotic  focus  with  subsidence  of  the  acutely 
inflammatory  phase  of  the  reaction  will  result  and  the  further  treat- 
ment by  nonspecific  injections  will  merely  aid  in  the  absorption  of 
this  soluble  material  from  the  focus.  It  becomes  clearly  evident 
therefore  that  the  identical  reaction  may  alter  an  inflammatory  focus 
in  seemingly  diametrically  opposite  ways — restitution  without  sup- 
puration, as  well  as  the  acceleration  of  suppuration  with  absorption 
following. 

The  Reaction  in  Inflammation  of  Nonbacterial  Origin. — Nor 
must  it  be  presumed  that  this  process  as  here  depicted  holds  _true 
merely  for  a  bacterial  process.  A  similar  reaction  takes  place  when 
we  deal  with  gout  and  when  we  deal  with  a  chemical  injury  such 
as  that  following  a  typical  "war  gas"  effect,  as  for  instance  mustard 
gas.  Von  den  Velden's  observations  will  be  of  interest  in  this  respect. 

"I  had  considerable  opportunity  in  the  field  to  study  the  effect 
of  nonspecific  therapy  in  mustard  gas  poisoning,  being  led  to  try 
the  method  not  only  by  the  clinical  observation  but  by  the  autopsy 
findings  as  they  presented  themselves  to  us.  I  need  but  briefly  men- 
tion in  this  connection  that  the  effects  of  the  gas,  as  shown  in  the 
effects  on  the  mucous  membrane  of  the  respiratory  tract,  varies  from 
the  mildest  catarrhal  inflammation  to  widespread  and  extensive 
croupous  and  finally  ulcerative  changes.  In  view  of  the  oftentimes 
decidedly  malignant  and  complicated  course  of  the  clinical  picture, 
I  endeavored  to  treat  as  early  as  possible  the  cases  in  which  the 
toxic  manifestations  were  most  severe,  or  those  in  which  the  clinical 
picture  was  one  becoming  progressively  worse  from  day  to  day,  in 
order  to  avert  the  secondary  pneumonias  and  the  abscess  formation 
and  especially  the  ominous  bronchial  stenosis  so  common  a  sequel. 
From  my  previous  experience  with  nonspecific  therapy  an  early  inter- 
ference by  means  of  an  acceleration  of  the  inflammatory  processes 
might  be  expected  to  yield  very  gratifying  clinical  results.  Of  course, 
these  might  be  of  purely  symptomatic  nature. 

"While  my  experience  extended  over  a  larger  number,  I  have 
recorded  observations  on  approximately  100  cases  of  gas  poisoning 
treated  either  with  horse  serum  (5-10  c.c.  intravenously),  milk  (10- 
20  c,c.  intramuscularly)  and  tetanus  antitoxin  (5-15  c.c,  intrave- 


116  PROTEIN  THERAPY 

nously)  with  from  one  to  three  injections.  The  cases  included  mod- 
erately severe  incipient  cases  with  severe  hoarseness  and  beginning 
bronchial  stenosis  without  secretion;  severe  cases  with  croupous  in- 
flammation extending  from  the  pharynx  deep  into  the  bronchial  tree, 
some  of  them  already  complicated  by  pneumonia;  as  well  as  older 
cases  with  severe  bronchorrhea  (with  as  much  as  3  liters  of  se- 
cretion per  day)  with  evident  peribronchitis,  pneumonia,  abscesses 
and  in  some  instances  lung  gangrene.  It  is  natural  that  in 
these  latter  cases  the  injection  had  little  or  no  effect  and  that  the 
most  satisfactory  results  were  achieved  in  those  of  the  first  category. 
Inasmuch  as  a  spontaneous  recovery  is,  however,  very  common  in 
this  class  of  patients  this  result  was  to  be  expected.  It  was  in  the 
second  class  of  patients,  however,  that  the  most  convincing  evidence 
as  to  the  value  of  the  injections — and  this  not  only  in  my  own 
estimation  but  in  that  of  my  attending  colleagues  as  well — was 
forthcoming.  In  from  6  to  10  hours  after  the  injection  the  first 
favorable  results  of  the  injection  were  to  be  noted,  first  in  a  diminu- 
tion of  the  stenotic  symptoms — lessening  of  the  cyanosis,  improve- 
ment of  respiration,  diminution  of  the  cough  and  a  freer  secretion. 
Very  instructive  was  the  solution  of  a  membrane  that  had  been 
present  in  the  pharynx  of  a  patient  and  which  could  be  observed 
readily.  And  to  this  local  effect,  which  was  of  far-reaching  thera- 
peutic benefit  in  the  further  progress  of  the  lung  pathology,  as  well 
as  indirectly  on  the  circulation,  there  was  added,  sometimes  only 
after  two  or  more  injections,  a  more  or  less  pronounced  critical  drop 
in  the  temperature  curve,  an  effect  the  origin  of  which  one  may  ex- 
plain in  a  variety  of  ways.  I  unfortunately  have  not  been  able  to 
tabulate  the  results  as  compared  to  cases  not  treated  with  injections 
because  of  fortuitous  circumstances. 

"The  success,  which  surely  cannot  be  specific  in  any  way,  corre- 
sponds to  experience  gained  with  nonspecific  injections  in  other  dis- 
eases and  the  effect  on  the  pathological  process  is  similar: — a  marked 
local  effect  on  the  more  or  less  severely  inflamed  mucous  membrane 
of  the  respiratory  tract  with  an  acceleration  of  the  dissolution  of 
membranes,  a  cleaning  of  ulcerative  processes  and  perhaps  an  in- 
hibition of  inflammatory  processes  just  beginning.  The  success  was 
so  frequent  and  apparent  that  chance  was  to  be  excluded. 

"On  the  skin  lesions  the  injections  seemed  to  have  no  effect.  With 
collargol  intravenously  injected,  I  gained  the  impression  that  ef- 
fects similar,  but  not  so  striking,  were  to  be  obtained,  and  it 
may  be  of  interest  to  note  that  Aschoff  obtained  comparable  re- 
sults in  the  treatment  of  gas  poisoning  by  injecting  diphtheria  anti- 
toxin." 

General  Inflammations  of  Bacterial  Origin.— So  much  for  the 
therapeutic  effect  to  be  observed  on  local  pathological  processes. 
When  we  deal  with  general  infections  we  meet  conditions  less 


THE  PROBABLE  MECHANISM  OF  THE  REACTION    117 

simple  and  in  which  speculation  and  conjecture  must  enter  to  a 
larger  extent.  Perhaps  it  will  be  most  satisfactory  to  discuss  the 
status  of  our  information  in  a  definite  variety  of  diseases,  each  dif- 
fering in  fundamental  pathology,  and  each  yielding  different  results 
when  nonspecific  therapy  is  used. 

(A)  In  typhoid  fever  we  deal  with  an  infection  originating  with  a 
gastro-intestinal   infection  followed  by   an  infection  chiefly   of  the 
lymphopoietic  system  and  a  concurrent  bacteriemia.     Here  the  in- 
toxication is  principally  due:     (1)   to  native  proteins  derived  from 
the  typhoid  bacillus  and  to  which  the  organism  has  become  sensi- 
tized during  the  incubation  period  of  the  disease,  (2)  to  very  toxic 
protein  split  products  contained  in  the  body  of  the  bacterium  (endo- 
toxins),  and   (3)   to  split  products  from  the  bacterial  cell  when  it 
undergoes  proteolysis.     The  disease  is  one  to  which  an  active  im- 
munity can  be  established. 

(B)  In  pneumonia,  on  the  other  hand,  we  are  dealing  with  an  in- 
fection differing  from  this  materially.  Leaving  undetermined  its  method 
of  invasion — whether  primarily  a  blood  invasion  that  localizes  in  the 
respiratory  tract  or  an  extension  directly  along  the  respiratory  tract 
(which  seems  most  probable),  we  deal  with  a  localized  inflammatory 
process,  probably  without  sensitization  of  the  body  to  the  native 
protein  of  the  pneumococcus,  a  process  in  which  the  toxic  manifesta- 
tions are  due  to  an  absorption  of  the  higher  split  products  derived 
from  an  inflammatory  exudate    (fibrin,  cell  detritus,  etc.)    located 
actually  on  the  surface  of  the  body  (considering  the  pulmonary  alveoli 
in  their  actual  relation  to  the  surface  an  invagination,  not  from 
their  mere  anatomical  position  as  part  of  the  internal  organs).    Be- 
cause of  the  vascular  supply  the  alveolar  surface  is  naturally  an 
ideal  absorbing  structure,  so  that,  while  largely  isolated  during  the 
course  of  a  lobar  pneumonia  from  the  general  circulation,  absorption 
is   still   sufficiently   great  to   cause   a  profound  intoxication.     The 
pneumococcus  protein  itself  is  not  particularly  toxic  and  as  already 
stated  the  organism  not  necessarily  sensitized  to  it;  the  bulk  of  the 
toxic  manifestations  must  come  from  the  splitting  of  the  exudate 
in  the  pulmonary  alveoli.    It  will  be  recalled  that  Kaznelson  found 
the   split  products   obtained   from  fibrin  particularly  toxic.     Here 
we  deal  with  recovery  frequently  by  crisis  rather  than  by  lysis  and 
with  an  immunity  of  low  grade  and  of  relatively  short  duration. 

(C)  Finally  we  might  take  as  an  example  a  pure  septicemia  of  the 
streptococcus   type,   without  localization,  where  intoxication   is   as- 
sociated with  marked  virulence  on  the  part  of  the  organism  rather 
than  by  the  production  of  a  soluble  toxin  from  the  bacterium  or  a 
toxic  autolytic  product  from  tissues  of  the  invaded  host. 

Typhoid  Fever. — Our  observations  in  typhoid  fever  are  perhaps 
most  complete  and  from  them  we  may  be  able  to  construct  a  picture  of 
the  processes  that  follow  the  nonspecific  reaction.  Let  us  assume  that 


118  PROTEIN  THERAPY 

we  have  given  a  proteose  injection  to  a  typhoid  patient  during  the  first 
week  of  the  illness.  He  has  responded  with  the  typical  chill,  a  sweat, 
rise  in  temperature  curve,  and  a  leukocytosis.  Following  the  reaction 
his  temperature  comes  to  normal  and  remains  so,  the  patient  feels  well 
and  as  far  as  can  be  determined  is  clinically  cured.  In  some  20-30% 
of  typhoid  patients  injected  we  can  observe  precisely  this  result. 
What  has  cured  the  patient? 

1.  It  has  been  stated  that  despite  this  clinical  recovery  typhoid 
bacilli  may  in  some  instances  still  be  cultivated  from  the  blood  of  the 
patient   several   days   after   the   injection    (Rohonyi).     Decastello's 
work  throws  much  doubt  on  this  particular  point. 

2.  The  patient  may  still  present  rose  spots,  an  enlarged  spleen, 
a  positive  diazo  reaction  and  a  leukopenia   (Liidke) ;  Holler  in  his 
series  only  noticed  the  occasional  splenic  tumor  after  the  recovery. 

3.  Healing  of  typhoid  ulcers  takes  place  within  a  few  days  after 
the  injection,  as  determined  by  autopsy  in  patients  dying  of  inter- 
current   disease,    after   recovery   by    means    of   nonspecific   therapy 
(v.  Wiesner). 

4.  Fluctuations  in  the  antibody  concentration  of  the  serum  do 
not  account  for  the  recovery.    In  some  cases  they  are  increased,  in 
others  actually  diminished,  despite  comparable  clinical  results.     Nor 
is  the  hypothesis  valid  that  when  diminished  it  affords  evidence  that 
the  antibodies  have  been  used  up  during  the  process  of  recovery. 
Recovery  from  typhoid  takes  place  normally  in  leukemic  patients 
who  never  produce  antibodies   (Moresci,  Howell). 

5.  The  cells  of  the  organism  are  all  stimulated    (omnicellular 
plasmaactivation  of  Weichardt)   when  injected  intravenously.     The 
stimulation  can  be  measured  in  the  increased  activity  of  the  glandular 
parenchyma,  in  increased  motility  of  smooth  musculature,  in  the  in- 
creased work  capacity  of  the  heart  muscle. 

6.  The  permeability  of  the  cells  is  altered.     Due  to  this  effect 
and  the  coincident  stimulation  above  mentioned,  enzymes,  fibrinogen, 
thrombokinase  and  glycogen  are  thrown  into  the  circulation,  and  anti- 
bodies, if  the  organism  has  been  previously  sensitized,  are  also  dis- 
charged from  the  cells  and  flood  the  blood  stream. 

7.  The  altered  permeability  of  the  cells   finds   further  expres- 
sion in  the  augmentation  of  the  lymph  flow,  directly  to  be  observed 
about  an  inflammatory  focus  or  to  be  measured  at  the  thoracic  duct. 
It  is  also  manifest  when  the  permeability   (to  certain  dyes)   of  the 
capillaries  about  an  inflammatory  focus  is  studied.    The  endothelium 
becomes  at  first  more  permeable,  later  less  so. 

8.  This  change  in  the  permeability  of  the  cell  membrane  whereby 
the  exchange  outward  and  inward  is  augmented  must  of  course  de- 
pend  on   actual   changes   in  the   physical   structure   of   the   lipoid- 
phase  which  probably  forms  the  membrane  of  the  cell. 

9.  This  change  in  the  membrane  of  the  cell  probably  accounts 


THE  PROBABLE  MECHANISM  OF  THE  REACTION    119 

for  the  increased  resistance  to  intoxication  after  the  injection  and 
forms  part  of  the  mechanism  of  antianaphylaxis.  Whether  an  actual 
loss  of  lipoidal  constituents  of  the  cell  membrane  takes  place  which, 
when  thrown  into  the  circulation,  then  form  part  of  the  antiferment, 
is  not  determined. 

10.  An  increase  in  the  antiferment  of  the  serum  occurs  after  the 
injection  and  persists  as  a  rule  for  some  days. 

"11.  The  alteration  in  the  cell  membrane  is  evidenced  further- 
more by  the  change  in  the  irritability  of  the  central  nervous  system 
and  in  the  sympathetic  nervous  system. 

12.  There  is  finally  a  mobilization  of  leukocytes  due  to  a  more  or 
less  specific  stimulation  of  the  bone  marrow. 

While  all  these  changes  are  brought  about  there  seemingly  are 
two  that  are  of  vital  importance — the  stimulation  of  the  cells — plasma 
stimulation  of  Weichardt — and  the  alteration  of  the  permeability 
of  the  cellular  membrane.  All  the  others  are  of  interest  and  very 
likely  to  take  some  part  in  the  result,  but  all  are  more  or  less  due 
to  these  two  fundamental  changes. 

There  is  an  increased  tolerance  to  intoxication.  The  patient,  de- 
spite the  fact  that  he  may  still  have  a  positive  blood  culture,  no 
longer  is  sensitive  to  intoxication.  The  experimental  basis  for  this 
clinical  observation  has  been  laid  by  Starkenstein  who  demonstrated 
that  after  a  variety  of  nonspecific  injections  the  organism  becomes 
more  resistant  to  intoxication,  even  to  poisons  such  as  phenol  and 
strychnin.  This  is  probably  due  to  the  decrease  in  the  permeability 
of  the  cell  membrane  that  follows  on  the  initial  increase  in  permeabil- 
ity. 

The  toxic  material  is  more  rapidly  destroyed.  Due  to  the  cellular 
stimulation  and  the  mobilization  of  the  proteolytic  enzymes,  pro- 
teolysis  is  hastened.  This  affects  (1)  the  native  protein  of  the 
typhoid  bacillus  to  which  the  body  during  the  course  of  the  incu- 
bation period  has  been  sensitized  and  (2)  the  toxic  split  products 
derived  from  the  bacillary  disintegration  (endotoxins)  which  are  now 
split  to  their  lowest  stages  and  eliminated. 

The  lymphagogue  effect  (increased  permeability  of  the  capillaries) 
floods  the  lymph  spaces.  If  we  conceive  of  typhoid  fever  as  a  local 
disease  and  not  a  septicemia,  the  curative  process  must  take  place 
at  the  site  of  the  lesion.  It  has  been  demonstrated  that  both  in  nor- 
mal and  immune  animals  the  antibody  concentration  is  greater  in 
the  plasma  than  in  the  lymph.  The  serum  in  typhoid  fever  is  in- 
variably rich  in  bacteriolytic  substances,  the  transient  and  low- 
grade  bacteriemia  notwithstanding.  With  the  active  passage  of  anti- 
body rich  plasma  into  the  lymph  spaces  the  destruction  of  the 
typhoid  bacilli  will  take  place  and  healing  will  be  explained.  (This 
theory  was  put  forward  by  Teague  and  McWilliams.) 

The  increase  in  the  anti-enzyme  in  the  lymph  spaces  makes  the 


120  PROTEIN  THERAPY 

further  proliferation  of  the  bacteria  difficult.  Bacteria  must  obtain 
their  nitrogen  from  the  lowest  degradation  products  of  proteins;  they 
cannot  use  peptones  and  proteoses  and  the  higher  split  products. 
When  the  antitrypsin  is  increased  their  extracellular  protease  is  in- 
activated and  their  metabolism  interfered  with  (Wright). 

On  this  basis  we  have  observations  that  account  not  only  for  the 
detoxication  of  the  patient,  which  is  commonly  observed  after  non- 
specific protein  injections  (the  euphoria  being  a  constantly  reiterated 
clinical  observation)  but  for  the  actual  destruction  of  the  bacteria  and 
the  checking  of  their  further  proliferation. 

Into  this  mechanism  other  factors  may  and  possibly  do  enter. 
Thus  the  question  of  the  effect  of  the  leukocytosis  has  repeatedly 
been  raised.  The  intravenous  injection  almost  invariably  results  in 
a  marked  augmentation  of  the  peripheral  leukocyte  count,  following 
the  initial  leukopenia.  This  has  been  considered  as  the  possible 
mechanism  involved  in  the  recovery.  But  it  has  been  observed  that 
recovery  may  take  place  without  the  appearance  of  this  leukocytosis. 
Inasmuch  as  the  blood  serum  itself  is  able  to  destroy  the  bacilli 
without  the  intervention  of  leukocytes,  their  usefulness  in  this  con- 
nection is  not  of  paramount  interest.  As  a  matter  of  fact  Rous  has 
shown  that  the  typhoid  bacilli  may  be  protected  from  the  effects 
of  serum  lysis  after  they  are  ingested  by  the  endothelial  leukocytes. 
It  is  much  more  probable  that  the  role  of  the  leukocyte  lies  in  its 
detoxication  of  the  bacillary  proteins  of  typhoid  bacilli  already  dead 
when  ingested,  or  so  altered  by  serum  contact  that  the  leukocyte  can 
finally  destroy  them  after  ingestion.  Of  course  the  concentration  of 
the  leukocytes  in  the  internal  organs — spleen,  liver,  lymph  glands, 
intestinal  tract,  lungs,  etc. — immediately  after  the  injection  (during 
the  time  of  the  peripheral  leukopenia)  at  the  very  site  of  the  chief 
local  foci  of  the  typhoid  proliferation  may  lend  particular  importance 
to  the  leukocytic  reaction  in  typhoid  fever. 

Lobar  Pneumonia. — Let  us  turn  to  examine  the  effects  of  non- 
specific therapy  in  lobar  pneumonia.  Blake  and  Russell  have  in  recent 
papers  thrown  considerable  light  on  the  questions  involved  in  the  mode 
of  infection  in  lobar  pneumonia  and  their  observations  confirm  the 
clinical  impression  prevalent  for  a  considerable  period  that  true  lobar 
pneumonia  takes  place  by  extension  of  infection  along  the  trachea.  Ac- 
cording to  their  study  the  pneumococcus  invades  the  lung  tissue  at 
some  point  or  points  near  the  root  of  the  lung,  spreading  subse- 
quently throughout  the  lobe  by  way  of  the  interstitial  framework  and 
the  lymphatic  system.  It  is  therefore  to  be  regarded  primarily  as 
an  interstitial  infection  of  the  lung.  Rosenow,  among  others,  as  a 
result  of  blood  culture  work  had  endeavored  to  place  pneumonia 
among  those  diseases  that  are  primarily  a  septicemia  and  later  be- 
come localized  in  some  tissue  of  predilection.  But  Blake  and  Rus- 
sell found  that  the  blood  became  infected  from  the  bacteria  having 


THE  PROBABLE  MECHANISM  OF  THE  REACTION    121 

gained  access  to  the  blood  stream  from  the  lymphatics  and  that  this 
bacteriemia  took  place  quite  early,  even  before  the  onset  of  clinically 
localizing  symptoms. 

Pneumonia  must  be  regarded,  therefore,  as  a  directly  localized 
disease  and  not  primarily  as  a  septicemia. 

It  is  the  critical  termination  of  the  disease  that  has  always  in- 
terested physicians  and  a  number  of  ingenious  theories  have  been 
elaborated  to  account  for  the  process.  But  as  long  as  we  sought 
the  solution  of  the  problem  along  strictly  immunological  lines  none 
of  the  hypotheses  put  forward  seemed  sufficient  to  account  for  all 
the  phenomena  observed.  At  times  antibody  concentration  was  altered 
before  or  during  the  crisis,  at  other  times  no  alteration  could  be 
demonstrated. 

In  more  recent  studies  a  different  line  of  thought  has  been  fol- 
lowed, and  it  has  been  made  probable  that  we  must  seek  part  of 
the  explanation  in  purely  physicochemical  alterations  that  seem  oper- 
ative in  the  mechanism  of  the  crisis.  Miiller  some  years  ago  em- 
phasized the  importance  of  the  proteolytic  enzymes  of  the  involved 
lung  area  in  bringing  about  resolution.  Later  Jobling,  Petersen  and 
Eggstein  advanced  the  hypothesis  that  the  intoxication  in  pneumonia 
was  of  dual  origin,  from  the  invading  organisms  and  also  from 
the  autolytic  products  of  the  involved  tissue  and  exudate.  Weiss, 
Lord  and  Nye  have  developed  this  same  thought.  According  to  this 
conception  recovery  in  pneumonia  is  associated  with  the  inaugura- 
tion of  active  proteolysis  of  the  pneumonic  exudate,  brought  about, 
according  to  Lord,  by  an  increase  in  the  local  acidity  to  such  a  de- 
gree that  the  autolytic  enzymes  find  a  suitable  medium  for  activity; 
according  to  our  conception,  by  an  increase  in  the  amount  of  auto- 
lytic enzyme  either  from  destroyed  leukocytes  (leukoprotease)  or 
from  mobilized  protease  from  distant  organs,  and  associated  with  a 
decrease  in  the  antienzyme  (antitrypsin),  by  saturation  with  the  ex- 
cess of  protease,  by  increase  in  acidity,  or  by  the  general  lowering 
of  the  antitrypsin  titer  of  the  body.  The  whole  phenomenon  in  its 
sharp  demarcation  between  profound  intoxication  and  complete  re- 
covery resembles  more  closely  a  chemical  reaction  in  vitro  than 
a  biological  reaction  in  vivo.  In  so  far  as  we  may  consider  the  in- 
volved tissue  as  being  isolated  from  the  general  circulation,  as  Kline 
and  Winternitz  have  pointed  out,  the  process  must  of  necessity  be 
largely  local  in  its  origin  and  effect.  Recovery  must  be  coincident 
not  only  with  the  destruction  of  the  bacteria  but  also  with  the  re- 
moval of  the  great  mass  of  fibrinous  and  cellular  detritus.  In  all  of 
its  essentials  it  is  therefore  an  autolytic  process  and  our  hopes  of  thera- 
peutic influence  must  be  based  not  only  on  the  idea  of  overcoming  the 
infecting  organism  but  also  of  favorably  influencing  the  autolytic 
changes.  The  very  isolation  of  the  lung  tissue  from  the  general  cir- 
culation after  the  disease  process  has  once  made  headway  favors 


122  PROTEIN  THERAPY 

autolysis,  for  if  the  tissues  were  freely  supplied  with  blood  serum, 
with  its  greatly  increased  antiferment,  autolysis  could  not  take  place. 
We  can  on  this  basis  understand  that  the  pneumonic  process,  apart 
from  complications,  will  tend  to  be  a  short  and  self-limited  one,  for 
even  if  the  invading  organisms  are  very  virulent  and  kill  off  the 
leukocytes  in  the  alveoli,  their  very  destruction  will  liberate  protease 
and  when  digestion  is  commenced,  terminate  the  disease. 

But  the  crisis,  although  as  a  rule  associated  with  the  disappear- 
ance of  the  organism,  need  not  on  this  basis  at  all  times  imply  that 
the  invasion  has  been  overcome.  The  one  is  a  physicochemical  process, 
in  the  other  we  deal  with  an  immunity  phenomenon.  Blake  and  Rus- 
sell describe  two  experimental  observations  that  are  illustrative  of 
precisely  this  condition — one  instance  of  recovery  by  crisis  in  which 
the  blood  culture  remained  positive  for  48  hours  after  the  crisis 
and  clinical  recovery;  the  others  were  cases  with  crises  on  the  7th 
and  9th  days,  respectively,  then  normal  temperature  for  several 
days,  followed  by  a  rise  in  temperature  and  death  of  the  animals. 
At  autopsy  a  resolving  pneumonia  was  found;  death  in  these  cases 
being  due  to  a  persistent  pneumococcus  septicemia.  Clinically  such 
cases  are  occasionally  encountered.  They  conclude  that  their  re- 
sults are  "not  out  of  harmony  with  the  theory  of  Lord  that  other 
important  factors  besides  the  development  of  humoral  antibodies  are 
necessary  to  bring  about  recovery.  It  is  not  unreasonable  to  con- 
sider pneumonia  as  comprising  two  distinct  though  intimately  re- 
lated processes,  one  always  present  being  the  local  lesion,  the  other, 
present  in  a  variable  number  of  cases,  being  a  general  infection  of 
the  body  as  manifested  by  the  occurrence  of  a  pneumococcus  septi- 
cemia. Though  ultimate  recovery  must  primarily  depend  upon  the 
ability  of  the  patient  to  prevent  or  terminate  the  general  infection 
once  established,  presumably  through  the  existence  or  the  develop- 
ment of  humoral  immunity,  it  does  not  follow  that  recovery  from 
the  local  process  with  resolution  of  the  pneumonic  consolidation  need 
be  either  coincident  with  recovery  from  the  general  infection  or  de- 
pendent on  the  same  mechanism.  In  fact  it  would  seem  well  estab- 
lished by  numerous  clinical  observations  that  recovery  from  the  gen- 
eral pneumococcus  infection  when  it  exists  usually  precedes,  by  sev- 
eral days  at  least,  recovery  from  the  disease  at  the  time  of  crisis. 
On  the  other  hand  certain  of  the  observations  cited  above  would  seem 
to  indicate  that  recovery  from  the  local  process  as  shown  by  a 
rapidly  resolving  pneumonia  may  occasionally  occur  prior  to  re- 
covery from  the  general  infection,  or  even  when  death  from  the  gen- 
eral infection  subsequently  takes  place.  In  view  of  the  above  con- 
siderations it  would  seem  not  improbable  that  at  least  a  dual 
mechanism  may  be  concerned  in  bringing  about  final  recovery  from 
lobar  pneumonia."  The  cultural  experiments  of  Thomas  and  Parker 
lend  support  to  this  view. 


THE  PROBABLE  MECHANISM  OF  THE  REACTION    123 

Now  let  us  observe  the  effects  of  the  nonspecific  reaction  in  this 
disease. 

In  the  case  illustrated  in  Figure  7  the  patient  was  admitted 
to  the  hospital  on  the  5th  day  of  April,  1917,  with  a  history  of  ill- 
ness for  5  days  previous  to  admission.  The  diagnosis  on  examina- 
tion was  a  frank  lobar  pneumonia  of  the  upper  left  lobe.  Two  days 
after  admission  he  was  given  a  small  dose  of  typhoid  vaccine  intra- 
venously (25  million)  following  which  he  experienced  a  slight  chill, 
some  rise  in  temperature  and  then  a  fall  in  the  temperature  until 
the  next  day  when  it  remained  normal  for  several  hours  in  the  morn- 
ing. After  this  remission  it  rose  again  by  the  evening  and  then 
came  down  by  lysis  at  about  the  normal  time. 

This,  it  may  be  as  stated,  is  a  typical  result,  and  portrays  the 
experience  that  we  have  had  when  small  doses  of  vaccine  are  so 
administered.  There  are  usually  a  moderate  chill  (not  as  severe  as 
in  typhoid,  for  example),  a  slight  rise  in  temperature,  then  a  critical 
drop  in  the  temperature  and  a  normal  temperature  curve  for  several 
hours.  Usually  the  former  or  a  temperature  slightly  lower  than  that 
observed  preinjectionally  is  then  maintained  and  the  disease  continues 
its  unaltered  course.  Euphoria,  a  decided  clearing  of  the  sensorium, 
improvement  of  the  pulse  and  of  the  vascular  tone  of  the  patient  are 
commonly  observed  after  the  injection  if  it  has  not  been  too  great 
in  dosage.  The  physical  findings  of  the  chest  are  as  a  rule  not 
altered. 

Miller  summarizes  his  experience  with  15  patients  so  treated  as 
follows : 

"Fifteen  consecutive  patients  with  lobar  pneumonia  entering  Cook 
County  Hospital  were  treated  by  a  single  intravenous  injection  of  typhoid 
vaccine.  The  dosage  used  was  30  millions,  the  minimum  amount  required 
to  give  a  chill.  All  reacted  by  a  rise  in  temperature  and  a  leukocytosis. 
In  nine  patients  the  vaccine  did  not  modify  the  course  of  the  disease.  In 
six,  the  patient  was  detoxicated  following  the  injections.  The  pulse,  tem- 
perature and  respiration  returned  to  normal,  the  cough  and  pleural  pain 
subsided,  and  the  patient  stated  that  he  felt  much  better.  In  three  of  the 
six  cases  the  improvement  was  temporary,  as  after  the  lapse  of  from  twelve 
to  twenty-four  hours  the  symptoms  returned  with  unmodified  severity. 
In  three  cases  the  detoxication  was  permanent;  however,  the  patients  had 
a  moderate  temperature  for  from  three  to  four  days,  to  the  time  at  which 
the  crisis  would  normally  appear.  They  were,  however,  entirely  free  from 
evidence  of  intoxication.  There  was  no  relation  between  the  severity  of 
the  chill,  the  temperature  reaction  and  degree  of  increased  leukocytosis, 
and  the  beneficial  results  of  the  vaccine." 

One  might  characterize  the  changes  as  a  temporary  detoxication 
that  leaves  the  general  course  of  the  disease  process  unaltered,  a 
result  that  might  be  anticipated  from  the  pathology.  The  biological 
alterations  previously  described,  i.e.,  the  enzyme  mobilization,  the 


124 


PROTEIN  THERAPY 


SERUM  PEPTIDASE 


Jplta 


7 


7 


7 


PEH  CENT, 
Inhibition 


ANTIFETUtENT  OF  SERUM 


F10-  7. — Serum  ereptase  and  antiferment  titer  in  pneumonia  subject  to  vac- 
cine shock. 

alteration  in  the  permeability  of  the  capillaries  and  of  the  cells  of 
the  nervous  system  and  the  general  plasma  stimulation  might  lead 
to  a  detoxication  of  whatever  noxious  material  might  be  present  in 
the  circulation,  and  the  increase  in  the  threshold  of  cellular  resistance 
to  intoxication  lead  to  a  state  of  relative  detoxication  so  that  the 


THE  PROBABLE  MECHANISM  OF  THE  REACTION    125 

patient  would  for  the  time  being  seem  improved — have  a  lowered 
temperature,  euphoria,  increased  vascular  tone,  etc.,  but  it  is  hardly 
to  be  expected  that  the  changes  would  be  sufficiently  great  to  effect 
the  immense  and  relatively  inert  local  disease  process,  isolated,  as  it 
in  a  measure  is,  from  the  general  circulation.  Here  the  production  of 
toxic  materials  would  proceed  largely  unmodified;  these  would  ac- 
cumulate, would  finally  get  out  into  the  general  circulation  to  a  suffi- 
cient degree  and  again  produce  symptoms  of  general  intoxication. 

If  pneumonia  were  a  disease  characterized  by  a  long  incubation 
period,  during  which  there  would  develop  not  only  sensitization  to  the 
protein  of  the  invading  organism  but  in  which  the  beginning  of 
immunization  could  take  place,  then  nonspecific  therapy — plasma- 
activation — might  aid  in  the  process  of  shedding  the  preformed  anti- 
bodies— would  possibly  mobilize  them  and  so  bring  about  recovery. 
But  beginning  as  it  does  without  an  incubation  period  of  any  extent 
this  factor  is  not  involved  in  the  mechanism.  From  the  single  large 
dose  we  can  therefore  expect  little  result  other  than  a  transient  one. 
But  of  course  there  are  exceptions.  One  such  may  be  of  interest  in 
this  connection.  It  concerned  a  boy  of  12  years  brought  to  the  hospital 
after  one  day's  illness  with  a  frank  lobar  pneumonia  of  the  upper  left 
lobe.  The  interne,  using  typhoid  vaccine  as  a  routine,  by  accident 
injected  a  large  dose  (500  million  organisms)  intravenously.  The 
child  reacted  with  a  severe  chill,  the  temperature  increased  to  107°  F. 
and  he  became  delirious.  The  next  morning  the  temperature  of  the 
patient  was  normal,  and  remained  so  without  further  fluctuation.  All 
physical  signs  of  consolidation  had  disappeared  within  24  hours  after 
the  injection.  Naturally  the  production  of  such  a  severe  reaction  is 
wholly  unwarranted  as  a  clinical  method  and  the  results  are  merely 
mentioned  to  illustrate  that  while  it  may  in  rare  instances  be  possible 
to  alter  even  the  large  pulmonary  processes,  such  a  result  is  quite 
uncommon. 

Of  course,  when  we  are  dealing  with  a  bronchopneumonia  the 
conditions  differ  to  some  extent.  So,  too,  the  possibility  that  repeated 
small  injections  used  as  stimulants  (plasmaactivation)  may  be  pro- 
ductive of  favorable  results  need  not  be  discussed  in  this  connection. 

Sepsis. — When  now  we  come  to  the  diseases  characterized  by  a  true 
multiplication  of  bacteria  in  the  blood  stream  and  observe  the  abrupt 
termination  of  such  septicemias  that  have  been  recorded  following  the 
intravenous  injection  of  the  nonspecific  agents  (Werner,  etc.),  the 
problem  becomes  one  of  decided  complexity.  Our  effect  on  local  in- 
flammation falls  away,  we  must  deal  wholly  with  the  destruction  of 
bacteria  multiplying  in  the  blood  stream.  Here,  too,  the  mere  detox- 
ication  of  the  patient  that  has  been  discussed  in  connection  with  pneu- 
monia, is  not  the  total  effect  of  the  injection.  This  detoxication,  the 
result  of  the  vascular  and  cellular  alterations  in  permeability,  of 
enzyme  stimulation,  etc.,  is  of  course  apparent  in  septicemia  as  well  as 


126  PROTEIN  THERAPY 

in  pneumonia,  but  the  occasional  abrupt  termination  of  the  disease, 
the  destruction  of  the  invading  parasite,  is  an  additional  factor  that 
must  be  accounted  for. 

That  foreign  protein  injections  have  an  influence  on  the  course  of  a 
sepsis  even  in  experimental  animals  has  recently  been  demonstrated  by 
Weichardt.  In  a  series  of  mice  injected  with  streptococci  he  found 
that  if  injections  were  made  before  the  streptococci  were  injected,  or 
as  late  as  24  hours  after  the  injection,  there  was  no  appreciable  differ- 
ence between  the  protein  and  the  control  animals ;  if  the  foreign  protein 
was  injected  from  4  to  8  hours  after  the  infecting  dose  of  streptococci 
a  definite  effect  on  the  duration  of  life  of  the  mouse  was  apparent. 

It  seems  probable  that  in  this  condition  the  effect  on  the  leukocytes 
and  on  the  antibody  concentration  is  of  greater  importance  than  in  the 
disease  processes  heretofore  discussed.  Where  the  body  has  been  in- 
fected for  some  time  the  cells  have  as  a  rule  become  sensitized,  have 
within  them  an  increased  amount  of  receptors,  fixed  antibodies.  If 
these,  as  a  result  of  some  "shock,"  are  thrown  into  the  circulation  the 
body  cells  will  become  less  sensitive,  not  being  able  to  fix  the  same 
amount  of  antigen;  on  the  other  hand  the  antibodies  now  free  in  the 
blood  stream  are  able  to  affect  the  bacteria.  The  augmentation  of  the 
agglutinin  and  opsonin  titers  in  particular  will  be  of  value  in  clumping 
the  bacteria  so  that  they  will  tend  to  accumulate  in  the  great  filtering 
centers  of  the  blood  stream — such  as  the  spleen,  bone  marrow,  liver, 
etc.  (Bull.) 

In  addition  to  this  fact  we  find  that  the  coincident  effect  on  the 
leukocytes  in  the  reaction  following  the  nonspecific  reagents  is  a 
primary  leukopenia  that  lasts  for  a  variable  period  of  time,  but 
usually  for  several  hours.  This  does  not  represent  a  destruction  of 
leukocytes,  but  merely  the  accumulation  of  the  cells  in  the  internal 
organs — lungs,  liver,  spleen,  bone  marrow,  etc. 

We  deal  here  with  two  factors  that  by  simple  mathematical  reason- 
ing (the  increase  of  proximity)  favor  phagocytic  destruction  of  bac- 
teria— the  accumulation  of  bacteria,  clumped  and  opsonized,  in  the 
blood  filters — the  accumulation  of  polymorphonuclear  leukocytes  in 
the  same  locations. 

While  these  processes  are  operative,  the  direct  stimulation  of  the 
hematopoietic  organs  may  be  of  value.  The  proliferation  of  leukocytes 
as  indicated  by  the  number  of  young  forms  (Arneth  count)  that  are 
to  be  observed  in  the  circulation  after  nonspecific  reactions  would 
mean  that  where  the  bacteria  have  accumulated  and  clumped — the 
bone  marrow,  spleen  and  liver — these  younger  leukocytes,  pre- 
sumably active  and  of  enhanced  phagocytic  power,  would  encounter 
the  invading  organisms  and  engulf  them. 

If  we  survey  the  mechanism  in  the  various  pathological  processes 
that  we  encounter,  in  strictly  local  inflammations  (bubo) ,  in  localized 
lymphatic  infections  (typhoid),  in  localized  organ  involvement 


THE  PROBABLE  MECHANISM  OF  THE  REACTION    127 

(lymphatic,  interstitial  and  external)  as  in  lobar  pneumonia,  or  finally 
in  true  septicemic  conditions,  we  find  that  no  one  factor  can  be  identi- 
fied in  the  mechanism  as  of  paramount  importance. 

In  the  local  reaction  the  alteration  of  the  permeability  of  the  cells 
and  the  complex  changes  in  the  inflammatory  reaction  that  this  entails 
seem  of  greatest  importance,  together  with  the  detoxication  of  toxic 
proteins  by  the  acceleration  of  enzyme  activity. 

In  the  typical  lymphatic  involvement  represented  by  typhoid  fever 
the  increased  permeability  of  the  vessels  and  the  flushing  of  antibody 
rich  fluids  into  the  lymph  spaces,  the  desensitization  of  the  patient  as 
a  result  of  later  cell  membrane  changes  and  the  general  increase  in 
cellular  activity,  in  vascular  tone,  in  the  tone  of  the  central  nervous 
system,  etc.,  are  perhaps  the  more  important  factors. 

In  pneumonia,  on  the  other  hand,  we  may  be  able  to  overcome  the 
effect  of  the  intoxication  for  a  temporary  period  by  increasing  the 
enzymatic  rate  of  destruction  of  the  toxic  proteins,  as  well  as  by 
increasing  the  resistance  of  the  cells  to  the  toxic  effect,  but  we  are  not 
able  sufficiently  to  alter  the  physicochemical  balance  that  exists  in  a 
more  or  less  isolated  lobar  lesion,  and  on  which  the  inception  of  the 
crisis  depends.  Here,  then,  we  have  to  deal  largely  with  a  transient 
detoxication. 

In  the  true  septicemias  it  seems  more  probable  that,  apart  from 
these  factors  that  tend  to  diminish  intoxication — that  is,  the  enzyme 
mobilization  and  the  decreased  permeability  of  the  cells — the  actual 
destruction  of  the  invading  bacteria  must  be  due  to  leukocytic  diges- 
tion and  perhaps  the  direct  effect  of  the  serum  antibodies  mobilized. 
The  clumping  of  the  bacteria  and  their  accumulation  in  the  internal 
organs  and  bone  marrow  bring  them  in  closer  proximity  to  the  leuko- 
cytes, which,  as  a  result  of  the  injection,  have  also  been  concentrated  in 
the  internal  organs  and  bone  marrow. 

It  is  at  any  rate  apparent  as  a  result  of  these  considerations  that 
different  disease  processes  are  diversely  affected  by  the  nonspecific 
agents,  depending  on  peculiarities  of  localization,  on  the  source  of  the 
material  that  is  responsible  for  the  intoxication,  on  the  degree  of  sen- 
sitization  and  immunization  of  the  patient.  While  nonspecific  agents 
may  produce  a  reaction  that  is  fundamentally  alike,  the  effect  on 
different  disease  processes  may  differ  considerably. 


CHAPTER  VII 

THE  RELATION  OF  THE  SKIN  TO  NONSPECIFIC 
RESISTANCE 

Skin  Reactivity. — The  fact  that  the  skin  and  its  reactivity  can  be 
influenced  by  a  variety  of  systemic  pathological  changes  and  through 
therapeutic  procedures  has  been  observed  by  physicians  for  many  cen- 
turies, indeed  ever  since  counterirritation  by  means  of  blisters  and 
chemical  irritants  was  introduced  (about  1600  A.  D.).  "We  often  find 
in  cases  of  intense  irritation  of  internal  organs  that  blisters  will  not 
vesicate  the  skin,  but  that  as  soon  as  the  disease  is  modified  they  will 
produce  their  usual  effect,"  wrote  Stokes  (as  quoted  by  Gillies) .  Trans- 
lated into  our  more  modern  procedure  we  find  this  same  phenomenon 
observed  when  we  apply  the  tuberculin  reaction  to  the  skin  of  a  patient 
during  any  acute  disease,  or  in  pregnancy  or  in  cachexia,  and  note  that 
the  reaction,  normally  obtained  in  practically  every  adult,  has  disap- 
peared. 

It  is  not  needful  in  this  connection  to  review  more  than  briefly 
recent  ideas  that  have  been  advanced  by  a  number  of  observers  con- 
cerning the  direct  reactions  of  the  skin  to  various  stimuli,  or  the  change 
of  the  skin  activity  following  certain  general  alterations  of  the  organ- 
ism. It  is  known  that  the  tuberculin  reaction  cannot  be  elicited 
during  acute  infections,  pregnancy,  cachexia,  serum  disease,  etc. 

Similar  observations  have  been  recorded  for  vaccines.  Thus 
Matthes  and  Rautenberg  have  recently  shown  that  the  digestion  prod- 
ucts of  typhoid  bacteria  which  were  used  as  a  vaccine  have  a  far 
greater  local  effect  in  the  normal  individual  than  in  those  ill  of  typhoid 
fever. 

Hoke,  working  with  the  intracutaneous  test,  found  that  the  trau- 
matic reaction,  as  well  as  the  intracutaneous  tuberculin  reaction,  were 
increased  in  leukemia  as  well  as  after  thyroid  feeding,  while  in  cases 
of  cachexia,  in  fever,  in  local  infection  and  in  deeply  pigmented  skin 
the  reaction  was  diminished. 

Depression. — Certain  general  conditions  of  the  body,  quite  diverse 
in  their  origin,  are  able  to  suppress  the  reactivity  of  the  skin  to  tuber- 
culin. These  general  conditions  are  obviously  not  specific;  that  is, 
they  need  bear  no  relation  to  tuberculosis,  nor  do  they  alter  the  anti- 
bodies and  in  this  way  effect  the  tuberculin  reaction  in  a  specific 
manner  because  it  has  never  been  shown  that  there  is  any  parallelism 

128 


RELATION  OF  SKIN  TO  NONSPECIFIC  RESISTANCE    129 

between  antibody  content  and  skin  reactivity.  Then  it  was  observed 
that  the  reactivity  of  the  skin  could  be  inhibited  by  injections  of 
various  kinds — the  heterologous  and  homologous  serums,  colloidal 
metals,  starch,  in  fact  after  nonspecific  injections  of  various  kinds. 

Luithlen  took  up  the  experimental  study  of  the  alteration  of  skin 
reactivity  from  the  vascular  side.  Using  croton  oil  as  an  irritant  he 
has  observed  that  after  the  injection  of  normal  serum  of  any  kind — 
homologous  and  heterologous — after  plasma  injections  or  blood 
transfusion,  after  gelatin  or  Witte  peptone,  after  colloidal  silicate  and 
after  starch  injections  the  reactivity  of  the  skin  was  markedly  de- 
pressed. Crystalloids  did  not  alter  the  reactivity,  in  some  instances 
actually  seemed  to  increase  the  reaction.  Luithlen  soon  recognized 
that  this  alteration  had  nothing  to  do  with  any  commonly  recognized 
biological  or  antibody  action  on  the  part  of  the  serum,  but  was  due  to 
an  alteration  produced  by  practically  every  colloid  injected. 

This  change  he  considered  dependent  on  an  alteration  in  the  per- 
meability of  the  capillaries.  In  determining  this  change  in  permeabil- 
ity he  proceeded  as  follows:  Rabbits  were  injected  with  Ringer's  solu- 
tion intraperitoneally  (100  c.c.)  and  then  2  c.c.  of  a  10%  solution  of 
sodium  ferrocyanid  was  injected  intravenously.  The  rate  at  which 
the  ferrocyanid  permeated  the  Ringer's  solution  in  the  abdominal 
cavity  was  then  determined  by  adding  hydrochloric  acid  and  ferric 
chlorid  to  samples  drawn  from  the  peritoneal  fluid  at  various  time 
intervals  and  noting  the  time  when  the  first  blue  coloration  was  ob- 
tained. The  normal  time  was  about  2  minutes.  Similarly  the  per- 
meability to  sodium  iodid  was  determined  and  found  to  be  about 
1  minute.  Variations  were  noted  with  the  age  of  the  animal  and  its 
state  of  nutrition. 

When  such  animals  were  now  injected  with  the  various  colloids 
which  had  been  found  to  depress  the  reactivity  of  the  skin,  it  was 
found  that  they  all  decreased  the  permeability  of  the  capillaries  as 
measured  in  the  manner  that  has  been  described.  Salts  did  not  alter 
the  rate  of  permeability  very  much,  but  repeated  bleeding  had  a 
definite  effect  on  diminishing  the  permeability. 

Activation. — If  the  reactivity  of  the  skin  can  be  altered  in  the 
sense  of  a  depression  we  must  accept  the  corollary  that  nonspecific 
factors  may  possibly  be  able  to  accelerate  the  cutaneous  reaction.  And 
of  this  we  have  abundant  evidence  in  the  effect  of  thyroid  feeding  and 
of  iodid  therapy  to  which  Sherrick  called  attention  some  years  ago 
and  which  has  been  confirmed  and  amplified  by  a  number  of  other 
workers — Kolmer,  Sollmann,  Stokes,  etc. 

We  are  therefore  led  to  the  inevitable  conclusion  that  elements 
wholly  nonspecific  in  our  ordinary  sense  of  immunological  specificity 
may  be  of  decided  importance  in  the  mechanism  of  the  skin  reactions. 

Clinically,  too,  we  have  been  forced  to  the  same  conclusion  as  a 
result  of  observations  on  a  variety  of  skin  reactions  which  have  been 


130  PROTEIN  THERAPY 

elaborated  during  the  course  of  the  past  ten  years.  Not  only  was  the 
luetin  reaction  found  to  be  unreliable  when  iodids  were  administered 
but  even  with  these  excluded  the  specificity  of  the  reaction  is  by  no 
means  to  be  depended  upon.  Thus  Blechmann  has  but  recently  pub- 
lished a  series  of  80  cases  in  which  he  injected  luetin.  In  this  group 
of  children  his  luetin  was  positive  in  about  35%  of  the  congenital 
luetics,  while  in  about  40%  of  nonluetic  children  he  also  obtained  a 
positive  luetin  test.  So,  too,  the  typhoidin  reaction  has  been  found  an 
absolutely  unreliable  index  of  the  immunity  of  the  patient.  Other 
skin  reactions,  such  as  the  gonococcus  reaction,  the  placental  reaction 
for  pregnancy  and  the  pneumococcus  reaction,  have  failed  for  the  same 
reason.  Only  where  we  deal  with  a  disease  depending  very  probably 
on  a  definite  hypersensitizatlon  of  the  patient,  such  as  in  asthma,  are 
the  skin  reactions  useful. 

When  skin  reactions  are  under  consideration  one  inevitably  thinks 
of  the  tuberculin  (either  the  v.  Pirquet  or  the  intracutaneous  test) 
reaction  as  the  most  typical  and  best  known  of  the  whole  group.  The 
general  reaction — subcutaneous  injection — should  by  no  means  be 
considered  in  the  same  category.  It  is  very  probable  that  the  tuber- 
culin reaction,  which  for  ordinary  clinical  purposes  we  may  consider 
specific,  has  a  very  large  element  of  nonspecificity  in  its  mechanism — 
much  larger  than  is  ordinarily  considered  probable,  as  has  been  fully 
discussed  in  the  chapter  on  The  Focal  Reaction.  Such  a  phenomenon 
would  by  no  means  be  an  anomaly  in  medicine;  indeed  our  Wasser- 
mann  reaction  is  an  example  of  just  this  same  condition.  Elaborated 
on  a  theory  of  strict  specificity  it  has  resolved  itself  into  a  specific 
clinical  test  that  is  based  on  a  physical  mechanism  in  which  the  anti- 
gen-antibody reaction  plays  no  part.  We  must  recognize,  too,  that  the 
evanescent  reactions  or  wheals  that  we  observe  in  determining  sensi- 
tization  to  proteins  (asthma,  etc.)  are  fundamentally  different  in  many 
respects  from  the  tuberculin  reaction. 

Clinically  it  has  been  determined  that  from  the  time  of  the  birth 
of  the  individual  the  organism  begins  to  alter  in  its  reactivity  of  the 
skin.  At  first  negative  to  tuberculin,  the  reactivity  increases  pro- 
gressively with  the  age  of  the  individual  until  in  adult  life  a  maximum 
is  reached  and  maintained  quite  consistently  except  for  certain  periods 
of  depression,  some  of  which  have  been  previously  mentioned.  But 
during  this  period  the  skin  does  not  only  become  sensitive  to  tuber- 
culin, but  increasingly  sensitive  to  a  series  of  other  bacterial  and  plant 
proteins  and  extractives;  so  to  colon  and  dysentery  and  cholera  pro- 
teins, to  bacterial  toxins,  peptones,  etc.  We  deal  obviously  with  a 
more  or  less  general  "sensitization"  or  "Umstimmung"  or  "allergy,"  as 
we  may  choose  to  term  the  condition. 

Now,  this  allergy  may  be  a  more  or  less  specialized  property  of  the 
skin,  indeed  may  be  localized  in  certain  areas  of  the  skin.  As  a  result 
of  it  the  tissues  acquire  the  ability  to  react  more  energetically  and 


RELATION  OF  SKIN  TO  NONSPECIFIC  RESISTANCE    131 

more  promptly  to  outside  stimuli — whether  specific,  as  with  tuberculin, 
or  nonspecifically  as  when  other  proteins  are  injected  in  and  about  an 
area  previously  injected  with  tuberculin,  or  finally  when  substances 
nonprotein  in  character  such  as  sugar  or  starch  are  used.  (Stokes.) 
Even  those  investigators  who  have  heretofore  been  the  most  ardent 
advocates  of  the  specific  character  of  the  tuberculin  reaction,  such  as 
Wolff-Eisner,  have  been  compelled  to  accept  the  inevitable  conclusion 
that  in  the  tuberculous  individual  the  skin  (and  the  body  as  a  whole) 
is  hypersensitive  not  only  to  tuberculin  but  to  proteins  in  general. 

In  a  paper  published  with  Sexsmith  we  have  pointed  out  a  possible 
basis  on  which  some  of  the  clinical  experiences  as  well  as  the  conflicting 
experimental  data  might  be  more  readily  understandable. 

Enzymes  in  Skin  Reactions. — Considering  both  the  phylogenetic 
and  ontogenetic  development  of  the  skin  and  its  function  it  is  apparent 
that  its  power  to  secrete  enzymes  is  one  that  is  more  or  less  inherent 
in  the  epithelial  cell — ultimately  highly  specialized  and  differentiated 
in  some  of  its  developed  organs,  rudimentary  and  potential  perhaps  in 
the  structures  that  serve  later  primarily  for  protection  rather  than  in 
the  active  metabolic  processes.  As  a  protective  structure  its  efficacy 
will  depend  to  a  large  extent  on  its  ability  to  react  both  very  rapidly 
and  very  strongly  against  either  invasion  or  intoxication.  When  one 
examines  the  enzymes  of  the  skin  one  observes  apparently  a  decided 
difference  in  the  enzymes  of  the  infant  or  young  skin  as  contrasted 
with  the  adult.  The  young  skin  contains  more  ereptase  (erepsin  or 
peptidase)  and  little  lytic  protease;  the  adult  skin  on  the  other  hand 
little  ereptase  and  more  protease.  Neither  type  of  skin  contains  much 
antienzyme. 

Let  us  suppose  that  we  inject  peptone  into  the  young  skin.  The 
ereptase  could  immediately  detoxicate  the  material  injected  and  there 
would  be  no  necessity  for  an  inflammatory  reaction.  If  we  inject  a 
native  protein  which  only  becomes  toxic  when  it  is  split,  the  infant 
skin  (containing  less  protease  than  the  adult)  is  not  able  to  split  the 
protein,  no  toxic  products  are  formed  and  there  is  no  reaction.  Indeed 
the  action  of  whatever  protease  is  present  in  the  young  skin  seems 
decidedly  synthetic  rather  than  lytic. 

If  now  we  examine  the  picture  in  the  adult  we  find  the  exact 
reverse.  If  a  peptone  is  injected  there  is  little  ereptase  present  to 
detoxicate  it  and  the  material  is  present  in  the  tissues  long  enough  to 
set  up  an  inflammatory  reaction.  If  on  the  other  hand  we  use  the 
native  protein  the  presence  of  sufficient  protease  in  the  skin  will  permit 
the  same  to  be  broken  up  with  the  formation  of  protein  split  products 
toxic  to  the  cells  and  an  inflammation  will  be  the  result.  The  relative 
paucity  of  ereptase  will  here  delay  the  detoxication. 

Inasmuch  as  our  ordinary  agents  that  we  use  in  eliciting  skin 
reactions  are  usually  mixtures  rather  than  pure  protein  or  protein 


132  PROTEIN  THERAPY 

split  products  the  enzyme  reaction  will  seldom  be  as  clear  cut  as  here 
portrayed. 

But  why  the  tissues  react  more  readily  the  second  time  is  a  question 
that  is  of  such  vast  biological  significance  that  we  can  merely  surmise 
some  of  the  more  superficial  and  obvious  alterations  that  are  involved. 
Even  were  we  to  consider  nothing  but  antibody  reactions  in  the  im- 
munological  sense  recent  work  would  indicate  that  this  alteration — 
allergy — is  not  necessarily  specific.  Bieling  has  demonstrated  that  any 
primary  sensitization  leaves  the  body  in  a  state  of  high  grade  hyper- 
sensitiveness.  Animals  immunized  to  cholera,  for  instance,  required  but 
a  minute  fraction  of  the  ordinary  dose  of  typhoid  antigen  to  bring 
about  a  high  degree  of  immunity  to  typhoid.  The  fact  that  a  second- 
ary injection  of  a  heterologous  protein  or  other  nonspecific  agent  will 
mobilize  the  antibodies  formed  against  a  previously  injected  antigen 
is  of  course  well  known  and  has  been  extensively  studied  by  Bieling, 
Hektoen,  Johnson  and  others.  The  cell  has  been  so  altered  that  its 
reactivity  is  increased,  as  though  a  dull  instrument  had  been  suddenly 
shaped  to  razor-like  keenness.  To  what  degree  this  involves  more  or 
less  permanent  alterations  in  the  physical  make-up  of  the  cell  ecto- 
plasm, in  how  far  the  protoplasm  of  the  cell  is  involved,  is  of  course 
purely  speculative. 

We  must  go  back  for  a  few  moments  and  consider  the  possible 
mechanism  of  the  suppression  of  the  skin  reactivity  to  which  we  have 
called  attention  in  relation  to  certain  conditions,  such  as  pregnancy, 
acute  infectious  diseases,  cachexia,  etc.  If  in  the  nonspecific  enzyme 
action  that  goes  on  in  the  skin  the  proteolytic  activity  can  be  sup- 
pressed, then  intoxication  and  inflammation  that  is  due  to  the  splitting 
of  native  proteins  to  the  toxic  forms  should  also  be  inhibited.  Such 
inhibition  can  take  place  when  the  chemical  reaction  of  the  medium 
is  not  suitable  or  when  we  have  an  excess  of  antiferment  present.  All 
of  the  states  during  which  the  skin  reactions  are  suppressed  are  con- 
ditions associated  with  an  increase  in  the  titer  of  the  serum  anti- 
ferment.  Stern  made  a  careful  study  of  the  suppression  of  the  tuber- 
culin reaction  during  pregnancy,  when  the  antiferment  titer  of  the 
serum  is  of  course  greatly  augmented.  Blb'te  confirmed  this  work  and 
showed  that  this  was  by  no  means  a  specific  phenomenon  because 
when  he  used  an  extract  of  jequirity  in  place  of  the  tuberculin  he 
obtained  a  similar  result.  This  increase  in  the  antiferment  titer  which 
oceurs  after  nonspecific  injections  of  various  kinds,  after  serum  sick- 
ness, during  antianaphylaxis,  is  coincident  with  the  alteration  in  the 
permeability  of  the  capillary  endothelium  to  which  Luithlen,  von  den 
Velden  and  others  ascribe  the  alteration  in  the  skin  reactivity  and 
which  must  also  have  a  large  share  in  the  mechanism. 

Meyer  has  studied  particularly  the  inhibition  in  the  cutaneous 
reactions  to  tuberculin  which  takes  place  after  prophylactic  typhoid 
vaccination.  Here,  too,  we  deal  with  a  nonspecific  reaction,  with  an 


RELATION  OF  SKIN  TO  NONSPECIFIC  RESISTANCE   133 

increase  in  the  antiferment  titer,  alterations  in  the  permeability  of  the 
vessels,  and  temporary  depression  of  the  irritability  of  the  vasomotor 
system  and  central  nervous  system  which  lasts  for  a  period  of  a  week 
or  so  after  the  injection. 

The  converse  of  this  clinical  observation  has  to  deal  with  the 
reactivation  of  skin  foci  by  nonspecific  injections  after  they  have 
undergone  involution.  Thus  it  has  been  observed  that  old  tuberculin 
papules  will  become  active  when  a  subcutaneous  injection  of  tuberculin 
is  given  in  some  remote  area  of  the  body,  when  milk  is  injected  or 
colloidal  metals  injected  intravenously.  To  what  degree  elements  of 
specificity  enter  into  this  reactivation  is  by  no  means  determined. 
Munzer  observed  that  when  partial  antigens  (Dyche-Much)  were 
injected  they  would  often  reactivate  old  intracutaneous  tuberculin 
papules  while  milk  injections  did  not  have  this  effect. 

Closely  related  is  the  effect  of  the  iodids  and  other  chemical 
agents  which  on  administration  activate  involuting  papules.  If  intra- 
cutaneous skin  tests  are  made  with  luetin  or  tuberculin  during  active 
iodization  of  the  patient,  the  skin  reaction,  instead  of  being  limited  to 
mere  papule  formation,  usually  goes  on  to  the  complete  pustule  stage 
of  inflammation.  Now  the  iodids  act,  as  do  the  related  chemical 
agents,  either  by  lowering  the  antiferment  titer  (Jobling  and  Petersen) 
or  by  nonspecifically  stimulating  the  tissues  (and  so  increasing  the 
amount  of  protease  and  other  enzymes  in  the  tissue  fluids)  or  finally 
because  of  their  effect  in  hastening  the  rapidity  of  diffusion  of  other 
salts  (and  colloids)  in  colloidal  systems.  The  end  result  is  of  course 
the  same — digestive  processes  are  hastened.  The  two  other  conditions 
—leukemia  and  thyroid  feeding — in  which  the  skin  reactivity  is  in- 
creased are  associated  with  a  diminution  of  the  antiferment  titer  and 
an  increased  enzyme  activity.* 

When,  therefore,  involuting  papules  flare  up  under  nonspecific 
injections  we  must  consider  the  possibility  that  the  following  changes 
may  form  the  basis  of  the  inflammatory  reaction.  With  the  height  of 
the  nonspecific  reaction  (negative  phase — digestion)  a  considerable 
amount  of  protease  is  mobilized  locally  and  generally  and  the  anti- 
ferment  is  diminished.  If  in  an  involuting  area  a  certain  amount  of 
undigested  protein  material  is  still  present,  digestion  will  commence, 
protein  split  products  will  be  liberated  at  the  focus  and  the  lesion  will 
again  flare  up — that  is,  we  will  witness  a  focal  reaction.  The  local 
cells,  it  is  to  be  remembered,  are  particularly  reactive  in  such  a  con- 
dition. 

When  the  patient  is  iodized  and  an  intracutaneous  test  made  we 
seem  to  deal  simply  with  a  condition  where  digestion  has  been  able 

*  The  fact  that  iodids  may  have  no  direct  effect  on  tissue  autolysis  in  vitro 
as  Albrecht  has  recently  demonstrated  has  no  direct  bearing  on  the  point  at 
issue  which  in  vivo  concerns  rather  the  mobilization  of  protease  from  normal 
tissues  and  their  effect  on  tissues  that  have  undergone  degenerative  change. 


134  PROTEIN  THERAPY 

to  proceed  much  farther  and  more  rapidly  than  in  the  uniodized 
patient.  When  the  injection  is  made  a  certain  amount  of  tissue  injury 
is  done.  Some  of  the  cells  will  be  injured  both  from  the  trauma  and 
from  the  toxic  material  injected.  In  the  uniodized  patient  the  in- 
hibition of  digestion  due  to  the  antiferment  checks  autolysis  to  a 
degree,  the  process  is  delayed  sufficiently  so  that  no  great  amount 
of  split  products  are  present  at  any  one  time.  The  rate  of  formation 
will  not  exceed  the  rate  of  diffusion.  In  the  iodized  patient,  on  the 
other  hand,  the  rate  of  digestion  being  greatly  accelerated,  protein 
split  products  will  accumulate  in  the  cutaneous  tissues  in  an  amount 
greater  than  the  rate  of  diffusion,  more  tissue  injury  will  be  done; 
with  autolysis  leukocytes  will  be  attracted  and  a  pustule  will  re- 
sult where  under  ordinary  circumstances  merely  a  papule  would  have 
been  formed,  or  a  papule  will  result  in  an  individual  in  which  the 
reaction  normally  would  have  been  absent. 

While  from  these  observations  it  is  apparent  that  nonspecific  fac- 
tors can  undoubtedly  influence  the  tuberculin  reaction  or  the  other 
skin  reactions  both  in  the  sense  of  depressing  them  or  accelerating 
the  reactivity  of  the  skin,  we  must  by  no  means  lose  sight  of  the  fact 
that  a  specific  element  enters  into  the  cutaneous  reactivity.  In  my 
opinion  it  is  probable  that  the  explanation  for  the  fact  that  the  tuber- 
culin reaction  ,  is  clinically  specific  and  fairly  reliable  while  similar 
skin  reactions  (typhoidin  reaction,  etc.)  are  not,  is  to  be  found  in  the 
fact  that  the  tuberculous  individual,  because  of  his  continuous  ab- 
sorption of  proteins,  is  in  a  state  of  generally  increased  sensitiveness 
to  proteins.  This  hypersensitiveness  is  of  a  degree  sufficient  in  tu- 
berculosis to  overbalance  the  nonspecific  factors  which  in  other  dis- 
eases interfere  so  greatly  that  the  interpretation  of  the  skin  reactions 
becomes  both  difficult  and  unreliable. 

The  Relation  of  the  Skin  to  Internal  Medicine. — While  in  a 
general  way  these  studies  have  been  undertaken  from  the  point  of 
view  of  the  dermatologist,  a  wider  viewpoint  that  includes  the 
relation  of  the  skin  and  its  reactivity  to  problems  in  internal  medi- 
cine has  found  expression  in  a  number  of  papers.  Particularly 
the  study  of  the  various  diatheses  has  interested  a  group  of  investi- 
gators. Thus  Schulz,  using  dilutions  of  carbolic  acid  to  bring  about 
skin  reactions,  determined  that  children  with  exudative  diathesis 
usually  revealed  an  increased  irritability  of  the  skin.  It  seems  prob- 
able that  the  severity  of  the  vaccina  reaction  and  the  reaction  to  the 
parenteral  injection  of  proteins  that  such  children  often  show  is  to  be 
associated  with  this  change.  But  the  hypersensitiveness,  according  to 
Schulz,  is  not  limited  to  children;  many  adults  suffering  from  eczema 
have  been  found  by  him  to  be  decidedly  hypersensitive. 

Brocq's  investigations  in  this  connection  are  of  importance.  It  has 
been  Brocq's  contention  that  in  such  hypersensitive  individuals — and 


RELATION  OF  SKIN  TO  NONSPECIFIC  RESISTANCE   135 

families — there  exists  a  so-called  "arthritic  milieu"  as  a  result  of  which 
they  are  particularly  susceptible  to  a  variety  of  pathological  altera- 
tions. They  react  to  outside  trauma  or  stimuli  of  such  mild  degree 
that  would,  in  the  normal  individual,  provoke  either  no  response  at  all 
or  at  the  most  a  very  negligible  reaction.  Eczema,  lichen,  urticaria, 
food  and  drug  idiosyncrasies,  herpes,  furunculosis,  pruritus  and  psori- 
asis are  regarded  by  him  as  belonging  in  this  category.  To  it  he  also 
adds  hay  fever,  asthma,  gout,  adiposity,  migraine  and  neuralgia.  Even 
Bloch  accepts  the  first  five  of  the  skin  diseases  as  belonging  to  this 
"arthritic"  group  of  diseases.  The  French  clinicians  have  carried  this 
conception  to  its  logical  conclusion  and  do  not  speak  of  eczema  as  a 
disease  entity  but  of  "eczematization"  (Besnier,  Darier,  Rapin  and 
V.  Hirschberg,  etc.). 

It  is  by  no  means  excluded  that  this  sensitization  takes  its  origin 
from  some  primary  bacterial  infection — tonsil,  gastro-intestinal  (gall 
bladder  and  appendix)  or  respiratory. 

Esophylaxis. — The  association  of  skin  reactivity  and  internal  con- 
ditions has  recently  been  illustrated  in  experiments  of  a  different 
nature.  During  the  course  of  investigations  on  the  mechanism  of 
intoxication  and  death  from  burns,  Pfeiffer  observed  that  a  marked 
mobilization  of  proteolytic  enzymes  occurred  after  even  superficial 
burns  of  the  skin.  As  a  result  of  this  observation  and  others  closely 
related  he  felt  justified  in  including  the  intoxication  of  burns  among 
those  due  to  protein  split  products.  In  view  of  the  relatively  rich 
enzyme  content  of  the  skin  such  a  mobilization  after  stimulation  might 
be  anticipated.  But  in  so  far  as  this  mobilization,  when  it  is  within 
physiological  limits,  or  under  therapeutic  control,  may  play  a  role  in 
influencing  internal  diseases,  the  study  of  the  skin  reactivity  becomes 
of  interest  to  us  not  only  in  the  sense  that  it  protects  against  disease 
entrance — an  "exophylaxis,"  as  Hoffmann  has  termed  it,  but  because 
of  its  importance  on  the  internal  organs  as  well — an  "esophylactic" 
effect. 

Bloch  and  Hoffmann  have  both  discussed  this  subject  in  recent 
papers  which  seem  of  considerable  interest  in  connection  with  the 
mechanism  to  which  attention  has  been  called.  Bloch  has  expressed 
the  conviction  that  the  skin  possesses  a  biological  function,  heretofore 
unappreciated,  by  means  of  which  the  vital  organs  are  protected  from 
bacteria,  or  at  the  most  have  but  to  deal  with  a  minute  amount  of 
attenuated  bacteria.  Taking  into  consideration  the  more  recent  work 
concerning  the  phenomena  of  allergy  as  observed  in  tricophyton  infec- 
tion, in  tuberculosis  and  syphilis  he  emphasizes  the  fact  that  "the 
skin  above  all  other  organs  plays  a  leading  role  in  allergic  immunity 
and  sensitization,  as  contrasted  with  serum  immunity,  such  as  that  of 
diphtheria,  tetanus,  etc.,  where  the  serum  is  the  carrier  of  the  anti- 
disease  mechanism." 

The  allergic  alterations — vaccination  against  variola — the  funda- 


136  PROTEIN  THERAPY 

mental  observations  of  Koch  on  the  production  of  tubercles  in  the 
skin,  which,  in  the  infected  animal,  assume  a  much  stormier  and  rapid 
course — the  researches  of  v.  Pirquet  on  the  vaccination  allergy  in 
tuberculosis,  syphilis,  and  fungus  infections — all  point  to  the  skin  as 
fundamentally  involved  in  the  mechanism  of  resistance.  Perhaps  it 
plays  some  role  even  in  recovery  in  the  acute  exanthemata,  such  as 
measles  and  scarlet  fever;  in  variola  its  importance  is  obvious.  Heim 
has  recently  expressed  the  opinion,  which  was  current  many  years  ago 
and  still  is  more  or  less  popular  in  folk  medicine,  that  the  skin  eruption 
of  the  acute  exanthemata  is  involved  as  part  of  the  mechanism  of 
recovery.  His  conception  is  that  the  organism  endeavors  to  rid  itself 
of  the  toxic  substances  through  the  skin,  that  a  leukocytosis  occurs 
there  and  that  the  latter  is  of  utmost  importance  in  digesting  the  toxic 
material.  While  in  bald  outline  the  theory  may  seem  crude,  it  is 
possible  that  there  may  be  some  connection,  as  Heim  has  suggested, 
between  the  skin  eruption  and  the  mechanism  of  recovery,  as  I  shall 
endeavor  to  point  out  later. 

Hoffmann  calls  particular  attention  to  the  clinical  observation  that 
the  internal  organs  are  frequently  spared  from  serious  involvement 
both  in  syphilis  and  in  tuberculosis  when  the  skin  lesions  are  extensive. 
In  order  to  emphasize  the  importance  of  the  skin  in  its  relation  to 
internal  medicine  he  calls  attention  to  a  number  of  other  facts  that  are 
more  or  less  pertinent.  The  fact  that  an  intoxication  ensues  when  large 
areas  of  the  skin  are  put  out  of  function  by  varnishing  or  burning; 
that  the  large  bulk  of  epithelial  tissue,  with  its  elaborate  network  of 
intercellular  canals  and  its  proximity  to  the  vascular  corium  would 
facilitate  absorption  of  secretions;  that  the  folklore  of  many  genera- 
tions expresses  the  idea  that  in  the  exanthematic  diseases  the  internal 
organs  are  spared  to  the  degree  that  the  eruption  is  manifest  in  the 
skin,  with  the  therapeutic  conclusion  that  anything  that  will  increase 
the  eruption  influences  the  patient  favorably  (Heim  also  calls  attention 
to  this  tradition) ,  all  indicate,  even  if  only  in  a  general  way,  that  the 
skin  may  be  of  importance  in  overcoming  infection. 

Hoffmann's  Theory. — Hoffmann  makes  the  epigramatic  statement 
that  "the  skin  is  the  grave  of  the  parasites."  The  fact  that  so  many 
acute  infections  involve  the  skin — measles,  scarlet  fever,  variola,  ty- 
phus, syphilis,  etc. — has  led  him  to  the  conclusion  that  the  skin  plays 
some  active  role  in  immunity.  In  how  far  some  internal  secretion  of  the 
epithelium,  to  what  degree  the  vascularized  papillary  body  with  its 
ready  inflammatory  response  enters  into  this  mechanism,  he  does  not 
suggest.  This  ability  to  respond  readily  with  inflammation  might  be 
anticipated  both  from  the  phylogenetic  as  well  as  from  the  ontogenetic 
development.  Thus  the  skin  of  the  adult  reacts  more  rapidly  and  to  a 
wider  range  of  substances  than  that  of  the  infant,  the  skin  of  the 
human  more  readily  than  that  of  lower  animals. 

Light  Rays. — Perhaps  the  effect  of  light  on  the  skin  and  the  recent 


RELATION  OF  SKIN  TO  NONSPECIFIC  RESISTANCE    137 

use  made  of  this  effect  in  the  therapy  of  internal  disease  is  of  particu- 
lar interest  in  disclosing  the  degree  to  which  the  skin  reactivity  can 
make  its  influence  manifest  on  the  metabolism  of  the  internal  organs 
and  pathological  processes  there  present.  When  a  patient  is  exposed 
to  light  rays  in  the  manner  developed  by  Bernhardt,  by  Rollier  and 
others,  certain  systemic  changes  occur  which  in  many  ways  resemble 
very  closely  the  reaction  that  we  have  described  for  the  protein  shock 
reaction  or  the  nonspecific  reaction.  Rollier  observed  an  increase  in 
eosinophils  as  well  as  in  hemoglobin  and  red  cells.  D'Oelsnitz  ob- 
served changes  in  the  temperature,  in  the  respiration  and  in  the  blood 
cytology.  The  temperature  and  the  respiration  are  both  increased  at 
the  beginning,  the  pulse  rate  may  be  accelerated  to  some  extent — all  of 
the  reactions  depend  greatly  on  individual  factors  and  particularly  on 
the  disease  from  which  the  patient  is  suffering;  in  tuberculosis,  par- 
ticularly on  the  type  of  the  tuberculous  lesion,  whether  active  or 
latent,  etc.  The  leukocytes  that  are  produced  are  usually  young  forms, 
although  in  the  reaction  mononuclears  predominate;  eosinophils  were 
also  observed  by  D'Oelsnitz. 

Dual  Effect  of  Heliotherapy. — Just  as  in  other  nonspecific  re- 
actions the  effect  of  the  sunlight  on  the  skin  and  the  effect  on  patho- 
logical conditions  is  a  dual  one.  Thus  it  may  activate  an  inflammatory 
focus.  In  active  progressive  tuberculosis  with  hemorrhage  and  a  septic 
type  of  temperature,  exposure  may  do  decided  harm.  In  its  genera] 
effect  the  reaction  set  up  is  similar  in  character  and  duration  to  that 
elicited  by  tuberculin  and  the  centra-indications  are  the  same.  Thus 
a  latent  tuberculosis  on  exposure  to  prolonged  sunlight  may  react  with 
a  typical  temperature,  increase  in  pulse-rate  and  the  general  malaise 
that  we  associate  with  the  tuberculin  reaction.  And  just  as  it  is  a  dual 
reaction  the  negative  phase  is  followed  by  a  positive  one.  That  is,  the 
difference  between  irritation  and  stimulation  and  overstimulation  is 
a  matter  of  very  small  margin  and  depends  on  the  individual,  as 
Pottenger  has  pointed  out.  Sunlight  has  no  specific  effect  on  tuber- 
culosis ;  it  is  not  a  cure  in  the  ordinary  sense  of  the  word.  It  is  merely 
a  stimulant  similar  in  character  to  many  of  the  other  nonspecific  agents 
which  are  able  to  cause  a  focal  reaction  and  thereby  influence  the 
process.  Its  difference  from  some  of  the  other  forms  of  therapy  lies  in 
the  fact  that  the  leukocytic  response  that  follows  heliotherapy  seems 
to  be  rather  a  lymphocytic  than  a  polymorphonuclear  reaction.  In 
nontuberculous  affections  it  has  been  recommended  in  general  con- 
valescence, where  it  is  followed  by  an  improvement  in  the  anemia 
(effect  on  hematopoietic  system)  and  in  the  weight  of  the  patient. 
Aimes  has  found  it  very  useful  in  acute  articular  rheumatism,  in 
tracheobronchial  adenopathies  and  in  neurasthenic  patients.  (Kellogg) . 
Lovett  has  reported  excellent  results  in  chronic  infections. 

Heliotherapy  as  Protein  Therapy. — It  seems  most  probable  that 
instead  of  seeking  to  find  the  cause  of  the  therapeutic  effect  of  the 


138  PROTEIN  THERAPY 

sunlight  in  some  hypothetical  internal  secretion  of  the  skin  which  is 
stimulating  the  entire  organism,  it  will  be  found  much  simpler  to  con- 
sider that  the  effect  of  the  sun  raying  of  the  skin  tissues  brings  about 
a  mild  (or  severe,  depending  on  the  degree)  form  of  nonspecific  shock. 
We  know  from  Pfeiffer's  work  that  actual  burns  will  do  this.  Between 
the  erythema  of  a  burn  due  to  actual  heat  and  that  due  to  sunlight 
there  is  not  much  difference  as  far  as  the  patient  or  the  effect  on  the 
organism  is  concerned.  The  epithelial  tissues  become  hyperemic  and 
absorption  from  them  is  accelerated.  Skin  enzymes — protease  and 
lipase,  perhaps  some  ereptase  in  younger  individuals, — are  swept  into 
the  circulation,  together  with  some  protein  split  products  due  to  diges- 
tive stimulation  in  the  skin.  The  agents  that  ordinarily  provoke  the 
nonspecific  reaction  are  therefore  available — the  enzymes  present  in 
the  serum  can  now  attack  seminecrotic  or  necrotic  foci  and  there 
accelerate  the  preexisting  inflammatory  reaction — i.e.,  set  up  a  focal 
reaction — a  tuberculin  reaction — with  its  resulting  train  of  increased 
temperature,  malaise,  etc.  As  a  result  of  the  protein  split  products 
derived  from  the  skin  the  organism  is  of  course  stimulated  in  the 
typical  nonspecific  manner  and  the  effect  on  the  hematopoietic  system, 
on  the  irritability  of  the  nerves  (Singer,  Pottenger),  on  the  general 
metabolism,  is  similar  to  that  which  we  have  seen  with  the  other  non- 
specific reactions.  Differences  exist  in  the  type  of  leukocytic  response, 
which  seems  to  be  more  lymphatic  in  the  case  of  heliotherapy.  An- 
other possibility  of  particular  value  in  tuberculosis  may  be  found  in 
the  relative  richness  of  the  epidermal  tissues  in  lipases  which,  when 
mobilized  after  heliotherapy,  might,  theoretically,  prove  of  decided 
value  in  resistance  to  tuberculosis. 

The  effect  of  heliotherapy  in  causing  a  focal  reaction  can  best  be 
illustrated  when  one  follows  the  effect  on  a  tuberculous  focus  such  as 
an  area  of  lupus.  Even  when  all  direct  effects  of  the  rays  are  excluded 
by  means  of  black  paper,  a  lupus  lesion  will  react  with  a  typical  focal 
reaction  after  a  general  sun  bath  just  as  it  does  after  tuberculin  injec- 
tion, after  milk  injection  or  any  of  the  other  nonspecific  agents.  Tuber- 
culous foci  have  been  observed  to  become  much  more  "sensitive"  or 
reactive  to  other  stimuli  such  as  x-rays  or  concentrated  red  rays,  etc., 
after  general  heliotherapy. 

Local  Applications. — Hoffmann  calls  attention  to  the  fact  that  other 
therapeutic  measures,  soap  inunctions,  mustard  baths,  sweating,  coun- 
terirritation,  etc.,  may  involve  precisely  the  same  mechanism.  When 
we  examine  the  acute  exanthemata  from  this  point  of  view,  it  will 
become  apparent  that  the  skin  manifestations  and  their  severity  may 
well  have  some  influence  on  the  general  course  of  the  disease.  Granted 
that  the  nonspecific  reaction  produced  by  injecting  various  substances 
may  terminate  an  infectious  disease  abruptly — and  the  clinical  evi- 
dence is  sufficiently  varied  by  this  time  to  permit  such  a  general  state- 
ment— we  have  seen  that  it  is  immaterial  how  this  reaction  is  elicited. 


RELATION  OF  SKIN  TO  NONSPECIFIC  RESISTANCE  139 

For  therapeutic  effects  certain  agents  have  been  found  more  effective 
than  others,  but  within  certain  limits  they  are  all  more  or  less  effective. 

Acute  Exanthemata. — If  in  an  acute  exanthema  we  regard  the 
huge  skin  involvement  in  the  nature  of  an  inflammatory  reaction,  it 
follows  that  from  it  not  only  enzymes  but  toxic  split  products  are  being 
absorbed  very  rapidly  when  the  hyperemia  that  is  part  of  the  inflam- 
matory reaction  becomes  pronounced.  When  the  skin  reaction  reaches 
its  height  we  know  that  it  is  accompanied  clinically  by  an  increase  in 
the  temperature  and  that  defervescence  usually  follows  in  the  wake  of 
this  increase.  The  normal  mechanism  of  recovery  in  these  acute  dis- 
eases may  therefore  involve  precisely  the  same  nonspecific  reaction  that 
we  now  seek  to  make  use  of  therapeutically  in  other  conditions. 

In  variola  the  appearance  of  the  skin  eruption  is  of  course  coinci- 
dent with  the  improvement  in  the  general  condition  that  is  so  char- 
acteristic of  the  disease — the  lowering  of  the  temperature,  the  pulse 
rate,  the  pronounced  euphoria,  etc. — and  the  secondary  fever  is  purely 
an  absorption  fever  when  suppuration  sets  in,  similar  in  its  character 
and  course  to  that  of  any  other  suppurative  condition. 

Focal  Activation  from  Intracutaneous  Injections. — Perhaps  one 
of  the  most  striking  illustrations  of  the  importance  of  skin  stimu- 
lation and  its  effect  on  remote  disease  processes  is  afforded  by  the 
recent  work  of  Miiller.  The  interesting  fact  has  been  brought  out 
by  him  that  the  intracutaneous  dosage  required  to  bring  about  a 
focal  activation  may  be  l/30th  less  than  the  dose  required  if  given 
intramuscularly  or  intravenously,  and  it  is  of  course  immaterial  what 
agent  is  used  in  the  skin  injection.  Thus  he  found  that  "arthigon," 
typhoid  and  cholera  vaccine,  tetanus  or  diphtheria  antiserums  and  even 
salt  solutions  were  able  to  elicit  focal  provocative  reactions  as  tested 
in  gonorrheal  urethritis.  His  results  emphasize  the  fact  that  relatively 
minute  and  seemingly  insignificant  skin  reactions  may  exert  a  tre- 
mendous effect  on  remote  pathological  lesions  and  that  we  must  seek 
the  mechanism  of  this  phenomenon  in  metobolic  alterations  produced 
in  the  skin,  not  in  peculiarities  of  the  agent  that  we  happen  to  use  to 
bring  about  the  reaction.  Needless  to  state,  the  tuberculin  therapy  of 
Ponndorf  (which  consists  of  intracutaneous  injections  of  tuberculin)  is 
related  to  the  alterations  that  Miiller  has  studied.  And,  as  we  might 
expect,  a  variety  of  clinical  conditions  have  been  reported  to  improve 
after  the  Ponndorf  technic.  Thus  Kroschinski  found  that  neuralgia, 
neuritis,  tabetic  pains,  acne  and  furunculosis  responded  to  the  tubercu- 
lin injections  made  in  this  manner. 

Syphilis. —  When  now  we  turn  to  examine  the  clinical  statement 
that  is  often  made,  namely  that  in  syphilis  accompanied  with  extensive 
skin  lesions,  or  in  tuberculosis  that  has  its  chief  site  in  the  skin,  the 
internal  organs  are  as  a  rule  free  from  pathological  changes,  we  find 
considerable  evidence  of  a  clinical  character  to  support  the  assertion. 


140  PROTEIN  THERAPY 

General  paralysis,  tabes  and  tertiary  lesions  are  said  to  be  very  un- 
common in  countries  in  which  the  skin  lesions  are  most  manifest ;  racial 
differences  seem  to  play  some  role,  too,  in  the  variation  of  distribution. 
In  our  American  negro  it  is  stated  that  the  parasyphilitic  manifesta- 
tions are  less  frequent  than  in  the  white  race,  although  vascular  lesions 
are  certainly  common  enough.  According  to  some  syphilogra- 
phers  even  malignant  syphilis,  when  in  its  early  stages  it  is  most 
manifest  in  the  skin,  is  prone  to  spare  the  internal  organs.  According 
to  a  number  of  investigators  the  possibility  must  be  considered  that 
this  effect  is  due  to  selective  affinity  of  certain  strains  of  the  spirochete 
(Nichols,  Matzenauer,  etc.) ;  Hoffmann  would  rather  implicate  the 
immunizing  effect  that  is  due  to  the  early  skin  involvement.  Clinically 
it  has  been  shown  that  tabetics  and  general  paralytics  seldom  give  a 
history  of  severe  luetic  skin  involvement;  usually  the  history  given 
is  that  the  skin  manifestation  was  merely  transient  and  that  there 
were  no  other  secondary  manifestations.  Bloch  assumes  that  it  is  the 
failure  of  the  skin  allergy  that  is  the  chief  cause,  particularly  of  nerve 
syphilis,  either  because  of  the  constitutional  inability  of  the  skin  to 
react  or  because  the  opportunity  was  not  given  the  skin  to  react. 

The  wide  distribution  of  the  spirochete  soon  after  it  gains  admission 
to  the  body  would,  in  my  opinion,  rather  exclude  this  latter  explana- 
tion. But  it  must  be  remembered  in  this  connection  that  the  spirochete, 
or  rather  the  reaction  that  the  spirochete  sets  up  in  the  tissues,  is  rela- 
tively easily  influenced  by  nonspecific  means.  One  has  but  to  recall  the 
effect  of  tuberculin  on  the  involution  of  the  syphilitic  papule,  the 
effect  of  the  injection  of  colloidal  metals  (particularly  silver)  on  the 
rate  of  proliferation  of  Spirochceta  pallida  in  experimental  animals,  the 
effect  of  intercurrent  diseases  on  the  manifestations  of  syphilis,  the 
pronounced  effect  of  the  iodids  on  the  absorption  of  gummata  and  in 
the  alteration  of  the  skin  reaction  to  luetin,  etc.  If  the  secondary 
lesion  and  the  gumma  are  so  easily  affected  by  these  means  it  is  very 
probable  that  the  inflammatory  reaction  in  the  skin,  no  matter  how 
produced  (even  if  by  the  specific  inciting  organism) — with  its  resulting 
absorption  of  enzymes  and  of  protein  split  products — may  act  as  a 
nonspecific  agent  and  have  some  therapeutic  effect  on  lesions  located 
internally.  It  has  even  been  suggested  that  the  efficacy  of  the  mer- 
curial inunction  over  other  methods  of  mercurial  therapy  is  due  to  the 
fact  that  the  skin  is  stimulated  mechanically. 

The  fact  that  the  tissues  of  the  central  nervous  system  afford  a 
very  favorable  milieu  for  the  spirochete  when  once  it  has  penetrated 
must  not  be  lost  sight  of.  The  meninges,  being  relatively  easily  pene- 
trated by  the  spirochete,  are  infected  early  and  often  in  syphilis.  It 
is  the  ectodermal  brain  substance  which  has  to  bear  the  brunt  of  the 
spirochetal  changes,  for  the  pia,  although  early  involved,  seems  to  rid 
itself  much  more  readily.  Both  the  brain  substance  and  the  cornea, 
containing  neither  lymphocytes  nor  adventitial  cells,  react  but  poorly 


RELATION  OF  SKIN  TO  NONSPECIFIC  RESISTANCE   141 

to  the  spirochete,  and  the  effect  of  syphilis  is  strikingly  similar  in  both 
cases,  as  Gartner  has  recently  pointed  out.  Specific  therapeutic  meas- 
ures have  been  found  equally  unsatisfactory  in  syphilitic  lesions  in 
both  tissues. 

If  we  are  able  to  bring  about  a  nonspecific  stimulation  we  at  times 
seem  to  be  able  to  secure  a  much  more  prompt  effect  on  the  luetic 
lesion;  the  therapeutic  application  of  the  principle  has  been  discussed 
under  the  respective  subjects. 

It  seems  probable  that  the  clinical  impression  of  increased  resist- 
ance to  syphilis  on  the  part  of  the  internal  organs  when  skin  involve- 
ment has  been  extensive  may  have  some  definite  basis,  in  that  a  severe 
inflammatory  reaction  in  the  skin  during  the  time  of  the  invasion  by 
the  spirochete  might,  by  nonspecifically  stimulating  the  body,  increase 
the  resistance  of  certain  of  its  tissues  that  normally  are  more  sus- 
ceptible to  the  spirochete.  If  this  reaction  occurs  sufficiently  early  the 
virus  might  be  prevented  from  gaining  a  firm  foothold  in  the  susceptible 
tissue  and  in  this  manner  later  parasyphilitic  lesions  might  become  less 
frequent  in  such  individuals. 


CHAPTER  VIII 
ARTHRITIS 

The  treatment  of  arthritis  has  been  one  of  the  most  satisfactory 
fields  in  which  nonspecific  therapy  has  been  applied.  The  contra- 
indications are  few,  the  evidence  of  improvement  is  strikingly  apparent 
to  the  patient  as  well  as  the  physician,  and  the  relief  from  the  pain 
so  welcome  that  the  discomfort  that  may  be  involved  in  the  method  is 
usually  willingly  borne. 

Miller  and  Lusk  were  the  first  to  report  on  cases  of  arthritis  treated 
with  proteoses  and  with  typhoid  vaccine  in  their  service  at  the  Cook 
County  Hospital  in  Chicago.  This  series  of  24  cases  gave  promise  of 
excellent  results,  and  in  a  second  paper  published  shortly  thereafter 
they  reported  on  the  results  in  85  additional  cases. 

Somewhat  smaller  doses  of  the  typhoid  vaccine  (from  40,000,000 
to  75,000,000)  were  given  to  their  patients  in  this  second  series.  They 
used  proteose  or  pollen  extract  in  a  few  instances,  and  the  results 
obtained  would  indicate  that  with  the  proper  dosage,  improvement 
similar  to  that  observed  after  the  use  of  the  typhoid  vaccine  would 
take  place.  In  the  second  series  there  were  45  cases  of  acute  arthritis, 
of  which  4  were  gonorrheal  in  origin;  the  period  which  had  elapsed 
from  the  onset  ranged  from  two  to  forty-five  days.  Previous  to  com- 
ing under  the  authors'  care  33  had  been  under  more  or  less  active  drug 
treatment,  usually  with  salicylates.  Of  those  who  had  been  under 
previous  drug  treatment,  29  reported  that  they  had  not  improved  under 
this  treatment,  and  4  had  been  moderately  benefited.  With  typhoid 
vaccine,  29  of  the  45  patients  recovered  promptly;  that  is,  the  pain, 
redness  and  swelling  disappeared  in  from  one  to  five  days,  and  usually 
within  from  twenty-four  to  forty-eight  hours.  From  one  to  four  injec- 
tions were  necessary  to  bring  about  these  results.  Of  the  remaining 
patients,  8  showed  great  improvement  with  only  some  stiffness  or  slight 
pain  remaining.  Six  showed  only  moderate  improvement;  in  2  no 
benefit  was  derived  from  the  treatment,  although  one  of  these  received 
eleven  and  the  other  thirteen  injections.  Nine  of  the  patients  had 
recurrence,  5  of  those  discharged  as  cured  and  4  of  those  discharged 
as  improved.  Seven  of  these  were  reinjected  and  either  recovered  or 
showed  marked  improvement.  In  the  4  acute  gonorrheal  cases  in  this 
series,  less  benefit  was  derived  from  the  treatment  than  in  those  of 
other  drigin. 

142 


ARTHRITIS  143 

Twelve  patients  with  subacute  arthritis  were  treated;  in  10  the 
condition  cleared  up  in  from  three  to  five  days  after  from  one  to  four 
injections,  although  in  2  of  them  there  was  still  slight  stiffness  or  sore- 
ness in  one  or  more  joints  at  the  time  the  treatment  was  discontinued, 
clearing  up,  however,  a  few  days  later.  Two  showed  marked  improve- 
ment after  two  or  three  injections,  but  subsequent  injections  failed  to 
bring  about  further  improvement.  Among  those  discharged  as  cured 
recurrences  were  recorded  in  2,  1  of  these  recovering  after  further  in- 
jection; the  other  patient  did  not  return  to  the  hospital,  for  further 
treatment. 

Nine  cases  of  chronic  arthritis  with  marked  acute  exacerbation  were 
treated  and  in  8  the  acute  symptoms  cleared  up  promptly  with  from 
one  to  three  injections. 

Nineteen  patients  with  arthritis  of  from  a  few  months  to  several 
years'  duration  were  grouped  as  chronic  arthritis.  Only  those  cases 
were  selected  in  which  there  was  definite  evidence  of  activity,  and 
ankylosis  was  not  marked.  Ten  of  these  patients  after  from  one  to 
five  injections  showed  a  definite  improvement,  the  acute  tenderness 
and  discomfort  on  motion  was  much  relieved.  The  patients  became 
less  helpless.  As  a  rule  not  all  of  the  affected  joints  were  bene- 
fited. The  results,  however,  were  such  that  it  would  seem  the  treat- 
ment had  been  actually  beneficial.  Not  all  of  these  cases  have  been 
followed,  but  there  are  several  in  which,  after  the  lapse  of  several 
months,  the  improvement  had  been  maintained.  Five  showed  mod- 
erate improvement,  and  4  were  not  benefited.  The  maximum  num- 
ber of  injections  given  any  of  these  patients  was  thirteen,  being 
given  daily  in  the  beginning  and  later  every  two  or  three  days.  In 
5  patients  included  in  this  group  the  arthritis  was  apparently  of  gon- 
orrheal  origin,  and  3  of  these  showed  such  marked  improvement 
that  they  might  be  pronounced  as  cured.  This  is  in  contrast  to  the 
resistance  to  the  treatment  of  the  acute  gonorrheal  cases.  One  of 
these  gonorrheal  cases  was  of  several  months'  duration  and  for 
three  months  previous  to  entering  the  hospital  the  patient  had  been 
compelled  to  use  crutches.  After  three  injections  he  was  able  to 
get  out  of  bed  without  assistance,  and  up  to  the  present  time  (four 
months)  has  not  had  a  relapse.  It  is  the  very  striking  results  ob- 
tained in  a  few  cases  of  this  character  which  have  led  the  authors 
to  believe  that  in  certain  instances  the  results  obtained  cannot  be 
equaled  by  any  other  of  the  present  methods  of  treatment.  The 
results  in  the  cases  of  chronic  arthritis  are  on  the  whole,  however, 
not  especially  striking.  The  tendency  to  recurrence  is  great,  per- 
haps owing  to  the  persistence  of  a  focal  infection.  It  is  essential, 
therefore,  that  where  this  method  of  treatment  is  employed,  it  be 
preceded  by  the  usual  efforts  first  to  locate  and  remove  the  local 
infection. 

The  reaction  provoked  by  the  intravenous  injection  of  the  typhoid 


144  PROTEIN  THERAPY 

vaccine  was  severe.  There  was  always  a  very  marked  rise  in  temper- 
ature and  with  few  exceptions  a  marked  chill.  The  headache  as  a 
rule  was  severe,  and  nausea  of  a  few  hours'  duration  was  not  in- 
frequent. In  3  cases,  all  alcoholics,  delirium  developed  at  the  height 
of  the  fever,  in  1  case  continuing  for  thirty  hours.  Marked  dyspnea 
was  observed  in  a  few  cases.  In  only  5  of  their  patients  did  Miller 
and  Lusk  deem  it  advisable,  on  account  of  the  violence  of  the  re- 
action, to  discontinue  the  treatment  after  a  single  injection.  No 
fatalities  occurred  as  a  result  of  the  treatment,  but  it  should  be 
borne  in  mind  that  evidence  of  cardiac  weakness  or  hypertension 
was  considered  a  centra-indication  to  the  treatment  and  such  pa- 
tients were  not  injected. 

Scully  later  reported  on  another  24  cases  of  whom  40%  cleared 
up  promptly  after  a  single  injection  and  Thomas,  working  at  St. 
Luke's  Hospital,  treated  an  additional  20  cases.  Of  these  30% 
were  permanently  relieved  from  pain. 

Other  American  workers  have  reported  on  extended  series  of 
cases.  Thus  Cecil  used  the  method  in  40  cases,  of  which  26  were  of 
the  ordinary  rheumatic  type,  7  acute  toxic  arthritis  and  7  of  gonor- 
rheal  origin.  Cecil  gave  typhoid  vaccine  intravenously,  using  a 
dosage  of  30  to  100  million.  By  accident  a  few  patients  received 
a  larger  dose  (400-500  million)  but  the  reaction  was  not  much  more 
severe.  Of  the  rheumatic  and  toxic  arthritides  40%  recovered  com- 
pletely in  from  two  to  ten  days  without  the  use  of  salicylates.  The 
remaining  20  patients  all  received  salicylates  at  some  time  of  their 
stay  in  the  hospital,  either  before  or  after  their  vaccine  treatment. 
Of  these  17  were  cured  or  greatly  benefited  under  the  combined  treat- 
ment. Cecil  noted  that  while  the  pain  in  the  joints  was  frequently 
completely  relieved,  a  degree  of  muscular  pain  persisted  in  the  mus- 
cles, particularly  in  the  muscles  of  the  back.  The  seven  patients 
suffering  from  gonorrheal  arthritis  made  very  slow  improvement  by 
the  vaccine  treatment. 

Cecil  concludes  that  the  method  is  undoubtedly  efficient  in  many 
cases  of  acute  arthritis,  but  that  it  is  unpleasant  for  the  patient  and 
may  be  dangerous  when  administered  to  improperly  selected  patients. 
It  is  interesting  to  note  that  several  of  his  patients  developed  herpes 
labialis  following  typhoid  vaccines  (we  had  the  same  experience  with 
certain  strains  of  vaccine;  others  never  were  followed  by  herpes). 
One  patient  developed  delirium  tremens. 

Snyder  has  reported  a  series  of  110  cases,  in  which  a  relatively 
small  dosage— 5  to  10  million  organisms— was  employed,  with  ex- 
cellent results.  Snyder  considers  the  method  more  satisfactory  than 
any  other  at  present  available.  No  kidney  injury  was  observed  fol- 
lowing the  injections. 

Pemberton  treated  19  cases  of  arthritis  with  intravenous  injec- 
tions of  typhoid  vaccine—using  25  million  organisms  of  the  U.  S.  Army 


ARTHRITIS  145 

yaccine.  Of  this  group  7  definitely  improved  (36%)  and  in  two  the 
results  were  uncertain;  in  the  rest  there  was  no  change,  although  one 
of  the  patients  was  apparently  made  worse.  In  more  than  half  of 
the  patients  the  temperature  rose  to  a  more  or  less  uniform  height — 
103°  to  104°  F. 

Pemberton,  working  with  military  cases,  calls  attention  to  the 
fact  that  many  of  these  soldiers  had  received  repeated  injections  of 
typhoid  vaccine  subcutaneously  without  effect  whatsoever  on  the 
arthritic  disability,  while  the  intravenous  injection,  which  seems  to 
stimulate  the  catabolic  processes  of  the  body  as  a  whole,  may  after 
a  single  injection,  produce  evident  clinical  improvement. 

Harding  also  treated  a  number  of  cases  (17)  while  in  military 
service,  but  reports  that  his  results  were  not  satisfactory. 

Cross  treated  14  cases  with  typhoid  vaccine,  using  an  intravenous 
dose  of  from  25  to  250  million  organisms.  The  results  were  quite 
satisfactory,  most  of  the  cases  clearing  up  very  promptly;  there  were 
no  ill  effects  and  no  endocarditis  was  observed  following  in  the  course 
of  the  disease.  While  he  observed  a  leukocytosis  following  the  in- 
jections he  does  not  consider  this  the  sole  factor  in  the  cure  of  the 
arthritis.  According  to  his  experience  "with  larger  doses  and  greater 
severity  of  the  chill  the  patient  has  experienced  greater  and  quicker 
relief  than  with  small  doses"  this  coinciding  with  the  experience  that 
other  observers  have  had  in  arthritis. 

Cadbury  treated  27  cases  of  arthritis  of  varied  etiology  with  intra- 
venous injections  of  typhoid  vaccine.  The  results  were  as  follows: 

4  acute  arthritis  (uncomplicated)  cured. 

1  rheumatism  with  cardiac  complications  and  sepsis — improved. 

f  2  cured 

16  chronic  arthritis -I  7  markedly  improved 
[  7  slightly  improved 

5  gonorrheal  arthritis{  \  jJJJ*^ 
1  luetic  improved 

Gow  has  also  published  his  experience  with  nonspecific  therapy, 
using  either  proteoses  or  heterovaccines,  and  concludes  that  in  cer- 
tain forms  of  arthritis  great  benefit  has  been  derived  from  intra- 
venous protein  therapy.  Vaccine  is  given  entirely  for  a  shock  effect. 
The  type  of  joint  disease  which  responds  best,  in  Gow's  experience, 
is  the  multiple  infective  arthritis  for  which  no  active  source  of  pri- 
mary infection  or  septic  absorption  is  demonstrable.  While  Gow 
regards  intravenous  protein  therapy  as  of  great  value  in  certain  care- 
fully selected  cases — more  particularly  of  arthritis,  the  septicemias 
and  coliform  infections — he  states  most  emphatically  that  it  is  not  a 
panacea  for  all  ills;  and  even  in  those  diseases  in  which  it  is  of  use 
it  is  to  be  regarded  solely  as  an  accessory  weapon  to  be  employed 


146  PROTEIN  THERAPY 

in  conjunction  with,  not  to  the  displacement   of,   other   remedies. 

Cowie  and  Calhoun  have  made  a  very  detailed  and  careful  study 
of  a  small  series  of  arthritic  cases  that  had  proved  intractable  to 
other  forms  of  therapy,  including  2  cases  of  chronic  multiple  peri- 
arthritis  deformans;  one  each  of  hypertrophic  arthritis  deformans, 
chronic  multiple  periarthritis  deformans,  atrophic  arthritis  and  hyper- 
trophic  spinal  arthritis;  two  of  acute  rheumatism;  two  other  cases 
were  treated,  one  a  gonorrheal  vulvovaginitis  and  the  other  a  sup- 
purative  mastoiditis,  complicated  by  chronic  pulmonary  tuberculosis. 
Typhoid  vaccine  in  relatively  large  dosage — 1  billion  organisms- 
was  used  to  give  the  reaction,  which  was  in  some  instances  quite 
severe.  Under  the  vaccine  treatment  most  of  the  arthritic  cases 
made  noticeable  improvement,  although  it  was  not  to  be  expected  that 
pathological  alterations  which  had  become  chronic  would  be  percept- 
ibly changed  or  modified.  The  case  of  vulvovaginitis  was  not  com- 
pletely cured  despite  several  injections.  The  chronic  suppuration  of 
the  ear  was  completely  cured  after  the  second  injection.  In  a  re- 
cent paper  Cowie  has  briefly  reviewed  his  experience  with  protein 
therapy.  He  finds  it  most  useful  in  acute  and  subacute  arthritis. 

Boyd  has  also  employed  typhoid  vaccine,  using  it  in  a  relatively 
moderate  dosage  (50  million)  with  success  in  a  variety  of  diseases 
originating  in  focal  infection,  including  arthritis. 

In  the  European  literature  one  finds  numerous  observations  con- 
cerning the  use  of  nonspecific  therapy  in  arthritis.  Typhoid  vaccine 
has  been  employed  less  frequently,  but  milk  injections,  following  the 
original  recommendation  of  Miiller  and  Weiss,  have  been  commonly 
used.  (Edelmann,  Panczyscyn,  etc.)  Colloidal  metals  have  also 
found  favor,  while  Edelmann  found  that  a  combined  form  of  therapy 
— using  salicylates  and  milk  injections — gave  results  that  practically 
assured  success  in  every  case. 

Voigt,  Moewes,  Voigt  and  Corinth  (iodid-silver  colloid),  Mukerjee 
(colloidal  sulphur  and  mercury),  Reichmann  (colloidal  silver),  re- 
port on  arthritis  treated  with  the  intravenous  injection  of  colloidal 
metals. 

Zimmer  used  casein  injections  both  intravenously  and  intramus- 
cularly, the  dose  varying  from  1  to  5  c.c.  of  a  5%  solution.  He 
reports  on  150  ambulatory  cases  treated  in  the  Polyclinic  and  some 
30  cases  treated  in  private  practice.  The  cases  included  arthritis  de- 
formans, old  rheumatic  and  traumatic  arthritides  as  well  as  a  num- 
ber of  other  origin.  His  general  experience  led  him  to  the  belief  that 
the  most  desirable  results  were  obtained  when  the  injections  elicited 
a  strong  focal  reaction  with  a  relatively  mild  general  reaction. 

His  cases  of  subacute  arthritis  and  gonorrheal  arthritis  were 
either  cured  or  markedly  improved.  The  immobility  incident  to  the 
older  gonorrheal  involvements  was  not  altered. 


ARTHRITIS  147 

In  arthritis  deformans  there  resulted  a  definite  improvement  in 
mobility  as  well  as  a  lessening  of  the  pain. 

Gout.—Iu  these  cases  a  focal  reaction  of  considerable  extent  wan 
precipitated  with  prompt  resorption. 

In  several  cases  of  neuritis  there  was  prompt  improvement. 

The  use  of  the  cartilage  extract  of  Heilner — "sanarthrit,"  in  chronic 
arthropathies  has  been  reported  upon  by  Umber  and  Meyer  and  also  by 
Reinhart,  by  Sonntag  and  by  Lampe.  Umber  reported  satisfactory  re- 
sults in  patients  and  Meyer  has  made  some  experimental  studies  on 
arthritis  in  animals.  Reinhart  treated  23  cases  of  chronic  arthritis  in 
whom  the  pathological  alterations  had  in  some  instances  been  of  very 
long  standing,  with  decided  bony  changes  visible  on  Roentgen  exam- 
ination. In  22%  of  these  cases  there  was  almost  complete  cure,  some 
of  the  patients  who  had  been  bedridden  for  long  periods  of  time 
being  able  to  be  up  and  about  after  two  or  three  injections,  and  the 
improvement  was  permanent.  In  48%  there  was  some  improvement, 
part  of  this  being  permanent  also.  The  other  cases,  despite  repeated 
injections  showed  no  improvement  whatsoever. 

There  was  no  doubt  in  Reinhart's  mind  that  the  effect  of  the 
"sanarthrit"  was  due  solely  to  the  nonspecific  reaction  that  followed 
the  injections. 

Roos  in  his  recent  discussion  of  the  treatment  of  arthritis  dis- 
cusses the  use  of  sanarthrit  and  reports  one  case  so  treated. 

Stern  has  treated  some  25  cases  of  arthritis  with  Heilner's  san- 
arthrit of  whom  10  showed  no  improvement.  In  4  cases  the  con- 
dition was  made  worse,  in  only  8  was  there  some  evidence  of  im- 
provement, and  this  was  usually  a  subjective  finding.  Denecke  has 
compared  the  effects  of  sanarthrit  and  casein  injections  in  30  cases. 
The  milk,  casein  and  "gonargin"  injections  resulted  in  less  focal  re- 
action and  he  does  not  consider  the  effects  quite  like  those  obtained 
with  sanarthrit. 

Discussion. — The  treatment  of  acute  arthritis  has  offered  one  of  the 
most  attractive  fields  of  therapy  for  nonspecific  procedures  and  the  re- 
sults have  in  general  been  very  satisfactory.  In  perhaps  40%  of  the 
cases  one  or  two  injections  completely  terminate  the  disease,  in  an- 
other 30%  the  improvement  is  marked  and  recovery  made  complete 
on  further  injections,  while  in  the  balance  there  may  be  either  a 
transient  improvement  with  a  relapse  later,  or  no  marked  clinical 
improvement.  It  is  true  that  the  methods  as  so  far  employed  are 
not  pleasant  for  the  patient — typhoid  vaccines,  or  vaccines  of  any 
kind  in  sufficient  dosage  to  cause  a  severe  reaction;  proteoses,  or  milk, 
are  all  followed  by  a  chill,  headache,  a  sharp  febrile  temperature 
reaction,  occasionally  nausea  and  a  general  feeling  of  malaise.  And 
yet  the  general  clinical  experience  has  been  that  a  sharp  general  re- 


148  PROTEIN  THERAPY 

action  is  followed  by  the  best  clinical  results.  Of  course,  efforts  have 
been  made  to  inject  substances  that  would  give  the  same  therapeutic 
effect  without  the  severe  reaction.  Brooks  and  Stanton  have,  for 
instance,  used  the  lower  fractions  of  digestion  products  obtained 
from  ox  fibrin  for  injections  in  arthritis.  With  this  product  they 
claim  to  have  obtained  satisfactory  clinical  results  with  practically 
no  unpleasant  systemic  reaction  on  the  part  of  the  patient.  The 
dosage  of  these  lower  split  products  was  about  12  milligrams  for 
intramuscular  injection,  while  one-fourth  or  one-third  of  this  dose 
was  given  for  intravenous  injection.  They  observed  improvement 
in  all  of  the  8  cases  of  arthritis  treated  with  this  preparation. 

Their  experience  differs  from  that  of  the  majority  of  the  clinical 
observers  in  their  ability  to  obtain  therapeutic  results  without  marked 
general  reaction.  It  has  been  our  experience  in  treating  arthritis 
that  unless  a  sharp  reaction  was  elicited  at  the  first  injection,  subse- 
quent injections  would  as  a  rule  be  followed  by  little  or  no  clinical 
improvement.  We  have  felt  that  arthritis  was  one  of  the  diseases 
where  such  a  sharp  reaction  was  justified  and  where  typhoid  vaccine, 
toxic  though  it  is,  seems  to  give  the  most  brilliant  results.  Usually 
the  arthritic  patient  is  an  excellent  risk,  is  not  very  toxic,  and  has  few 
centra-indications,  so  that  a  more  or  less  heroic  method  of  therapy  is 
entailed  with  less  danger  than  in  other  forms  of  disease. 

Apart  from  the  immediate  cure  of  the  disease  another  factor  of  im- 
portance enters  into  consideration  when  we  deal  with  arthritis,  namely 
the  carditis  that  so  often  complicates  the  picture.  Nonspecific  therapy 
seems  to  have  little  or  no  influence  on  an  endocarditic  process  once 
it  is  established  unless  small  doses  are  given  over  a  long  period  of 
time;  even  then  its  absolute  value  is  not  certain.  Single  large 
doses  may  at  times  influence  the  temperature  of  such  cases  for  a  day 
or  two,  but  not,  as  a  rule,  over  a  longer  period  of  time  (Kinsella). 
It  is  probable,  however,  that  the  early  termination  of  the  arthritic 
process  by  nonspecific  therapy  does  prevent  the  establishment  of 
endocarditis  in  a  definite  number  of  cases  and  in  the  prevention, 
rather  than  the  cure  of  endocarditis,  this  form  of  therapy  perhaps 
offers  a  valuable  aid. 

From  the  point  of  view  of  the  hospital  management  of  arthritic 
cases  another  factor  of  importance  must  be  emphasized,  namely,  the 
relative  cost  of  maintenance  of  the  arthritic  case.  If  by  any  form 
of  therapy  the  period  of  hospitalization  can  be  shortened  from  the 
average  of  5  or  6  weeks  to  a  period  of  a  week  or  two,  its  usefulness 
from  an  economic  standpoint  will  be  apparent. 

Possibly  an  unbiased  review  of  the  subject,  such  as  that  recently 
published  by  Torrey,  will  be  of  greater  value  than  my  personal  im- 
pression, which  perhaps  may  be  prejudiced  in  favor  of  this  form  of 
treatment. 


ARTHRITIS  149 

Torrey  first  recalls  the  rather  interesting  work  of  Terc,  who 
treated  a  large  number  of  rheumatic  cases  with  bee  stings,  following 
which  the  patient  often  reacted  with  a  typical  general  reaction — fever, 
general  malaise,  etc.  When  the  sting  was  repeated  over  a  period  of 
time  the  patient  became  more  or  less  refractory  and  during  this  re- 
fractory period  the  symptoms  of  the  arthritis  disappeared.  Langer 
later  repeated  this  work,  using  an  extract  of  the  bee  poison,  but  his 
clinical  observations  were  not  so  extensive  nor  so  conclusive  as  those 
of  Terc.  More  recently  Bold  has  investigated  the  poison  of  the  bee 
and  has  tried  to  sensitize  animals  to  the  bee  toxin,  but  without  re- 
sult. Torrey  then  continues:  "The  lack  of  result  with  sera  and 
vaccines,  unless  the  administration  is  followed  by  a  definite  febrile 
reaction,  and  the  good  result  following  such  reaction,  no  matter  what 
agent  is  used,  indicates  that  a  nonspecific  agent  alters  bodily  condi- 
tions materially.  It  is  not  clear  whether  actual  infection  is  influ- 
enced by  allergic  or  anaphylactic  reaction.  More  reason  exists  for  the 
view  that  the  change  affects  the  toxic  expression  of  the  infection, 
and  that,  while  the  organisms  are  still  retained  in  viable  form,  their 
presence,  or  products,  do  not  excite  response  by  marked  tissue  change. 
There  is  probably  a  prompt  detoxicating  action  exerted  in  the  blood 
or  tissues  by  the  allergic  response  to  the  introduction  into  the  blood 
stream  of  a  foreign  protein.  While  a  similar  response  may  be  elicited 
to  a  less  degree  by  subcutaneous  or  intramuscular  injection  of  toxic 
proteins  the  sudden  and  full  effect  is  attained  only  by  intravenous 
injection  where  the  protein  is  put  into  the  blood  unmodified  by  pas- 
sage through  other  tissues  and  unaltered  by  cell  or  membrane  selec- 
tion. The  usual  typhoid  prophylactic  initial  dose  of  500  million  killed 
typhoid  bacilli  given  subcutaneously  seldom  gives  a  severe  reaction; 
if  given  intramuscularly  there  is  more  apt  to  be  a  more  marked 
febrile  response,  while  one-tenth  of  that  dose  given  intravenously 
will  as  a  rule  promptly  produce  a  chill  and  a  sudden  rise  in  tempera- 
ture to  103°-105°F.  (39.4°-40.6°C.).  The  ultimate  gain  in  specific 
immunity  against  typhosus  infection  will  be  much  greater  in  the  for- 
mer case  but  a  detoxicating  action  and  termination  of  acute  inflamma- 
tory processes  will  follow  promptly  after  a  severe  reaction  to  the 
small  dose  given  intravenously  but  not  after  the  gradual  absorption 
of  the  larger  subcutaneous  dose. 

Two  questions  suggest  themselves:  (a)  While  experience  offers 
abundant  evidence  that  arthritis  can  be  promptly  terminated  by  such 
intravenous  therapy,  is  it  a  safe  procedure  and  does  it  for  this  pur- 
pose show  any  decided  advantages  over  salicylate  therapy?  (b) 
Granting  that  arthritis  may  be  controlled  by  this  means,  is  there  any 
indication  that  carditis  is  prevented  or  favorably  influenced? 

(a)  Regarding  the  safety  of  the  procedure.  Bacterial  extracts  or 
emulsions  vary  so  greatly  in  their  toxic  effects  that  great  care  must 
be  used  in  the  selection  of  the  strain  and  the  estimation  of  the  dose. 


150  PROTEIN  THERAPY 

As  Miller  states,  it  is  necessary  always  to  start  with  a  minimum  dose 
of  vaccine  until  its  toxic  index  has  been  gauged.  The  writer  has 
heard  of  a  fatality  resulting  from  the  intravenous  use  of  typhoid 
bacilli.  The  reaction  is  so  severe  that  it  would,  offhand,  appear  that 
the  margin  of  safety  was  a  narrow  one.  On  the  other  hand  long 
series  of  cases  so  treated  have  been  reported  by  Miller  and  Lusk,  by 
Cecil  and  other  American  observers. 

As  for  the  use  of  unknown  quantities  of  mixed  organisms  with 
no  means  of  duplicating  surely  the  strains  used,  it  would  seem  ex- 
tremely hazardous  to  use  such  products  intravenously ;  and  where  such 
severe  reactions  are  concerned,  very  difficult  in  any  event  to  judge 
dosage. 

It  would  appear  safer  to  use  a  definite  compound  as  suggested 
by  Jobling  (proteoses)  where  the  dose  can  be  accurately  determined 
by  weight  and  where  stability  can  be  assured. 

The  writer  has  used  formaldehyd  intravenously  to  accomplish 
the  same  reaction.  The  toxic  agent  introduced  here  is  probably 
a  combination  of  formaldehyd  and  serum  protein.  The  systemic  re- 
sults are  similar  to  those  accomplished  by  the  bacterial  injection. 
Two  years  ago  the  writer  with  his  resident  physicians  at  the  Phila- 
delphia General  Hospital  treated  29  cases  of  acute  and  chronic  ar- 
thritis by  this  method.  In  these  cases  careful  search  was  made  for 
signs  of  renal  changes,  blood  breakdown  or  other  signs  of  renal 
damage  but  we  could  find  no  evident  bad  effects. 

It  might  be  said  that  while  bad  results  have  not  been  shown  to 
follow  careful  intravenous  therapeutic  measures  we  are  dealing  with 
a  most  potent  agent  and  the  safety  of  this  procedure  has  not  been  as- 
sured. It  is  probably  not  justifiable  to  employ  this  method  of  treatment 
routinely  unless  more  is  to  be  accomplished  than  simple  relief  of  the 
arthritis.  In  most  cases  salicylates  and  good  nursing  will  accom- 
plish this  result  in  a  few  days'  time. 

(b)  As  regards  the  second  query,  Is  the  development  of  carditis 
prevented  or  favorably  influenced  by  this  form  of  treatment?  a 
much  larger  collection  of  cases  will  be  necessary  before  this  question 
can  be  answered.  It  is  said  that  established  active  endocarditis  is  not 
eradicated;  further,  that  when  endocarditis  is  present  arthritis  tends 
to  recurr  after  intravenous  treatment,  showing  that  the  infection  re- 
mains. 

The  writer  has  not  used  intravenous  therapy  in  cases  with  severe 
endocarditis  or  in  those  showing  evidence  of  severe  myocardial  de- 
generation. The  patients  were  selected  as  a  rule  among  younger 
adults  either  refractory  to  salicylates  or  showing  a  very  severe  degree 
of  arthritis,  or  those  who,  having  observed  results  in  other  patients, 
requested  this  form  of  treatment.  These  patients  were  usually  la- 
borers from  railroad  construction  gangs  or  workers  in  munition  plants 
and  it  has  been  impossible  to  follow  up  these  cases  properly,  but 


ARTHRITIS  151 

it  must  be  said  that  at  the  time  of  leaving  the  hospital  none  of  them 
showed  any  serious  cardiac  damage.  We  endeavored  to  keep  all 
rheumatic  patients  in  bed  for  three  weeks  after  the  temperature 
reached  normal  and  succeeded  in  most  cases  in  doing  so. 

Any  measure  that  will  protect  against  carditis  will  be  of  tremendous 
importance  and  while  in  this  case  we  may  be  merely  clutching  at 
a  straw  the  subject  should  be  studied  carefully.  It  is  recognized  that 
infection  is  prone  to  implant  itself  upon  the  heart  in  which  there  has 
been  tissue  damage  and  it  is  more  than  possible  that  endocardial 
damage  results  first  as  a  toxic  expression,  as  it  may  in  the  joints,  and 
that  the  liability  of  a  permanent  infection  may  be  reduced  by  the 
detoxicating  action  of  the  allergic  response.  The  writer's  feeling  is 
that  serious  cardiac  trouble  is  less  apt  to  develop  when  this  form  of 
therapy  is  used.  Realizing  the  risk  attendant  on  its  use  he  is  still 
i  Alined  to  try  it  on  young  and  vigorous  individuals  where  the 
myocardium  is  not  greatly  damaged." 

This  conservative  resume  of  Torrey's  is  quoted  in  full  because 
of  its  dispassionate  and  critical  perspective  and  because  it  emphasizes 
several  points  that  should  be  kept  in  mind — whether  it  is  a  dangerous 
method  of  therapy;  if  not,  is  it  a  better  method  than  our  present 
one,  and  finally,  does  it  prevent  cardiac  complications? 

While  we  by  no  means  believe  that  the  goal  in  therapy  has  been 
reached  when  we  inject  typhoid  vaccine  intravenously — other  agents 
may  be  much  better  and  may  be  much  less  uncomfortable  for  the  pa- 
tient— yet  we  have  never  seen  any  ill  effects  from  moderate  doses 
of  typhoid  vaccine  injected  intravenously  when  reasonable  care  was 
exercised  to  exclude  alcoholics  and  severe  heart  cases.  It  is  considered 
safe  enough  to  enable  one  hospital  to  make  the  injection  a  routine 
procedure  for  all  rheumatic  cases  entering  the  service. 

Our  present  expectant  therapy  or  salicylate  therapy  fails  in  a 
definite  percentage  of  cases.  In  a  good  number  it  is  temporarily  ef- 
fective and  is  followed  by  a  relapse.  In  others  cardiac  complications 
are  superimposed  even  during  the  course  of  the  salicylate  treatment. 
It  is  furthermore  a  protracted  therapy  and  therefore  an  expensive 
one. 

Nonspecific  therapy  does  frequently  effect  improvement  and  cure 
of  the  disease  where  salicylates  have  been  used  without  avail. 
Usually  one  or  two  injections  will  disclose  whether  or  not  we  can  ex- 
pect much  relief  by  the  nonspecific  agent  and  when  it  is  effective,  it 
is  rapidly  so.  My  own  impression  is  that  it  materially  lessens  the 
number  of  cardiac  complications,  although  I  cannot  present  definite 
statistics  to  that  end.  And  in  terminating  the  disease  abruptly  we 
lessen  the  number  of  chronic  arthritic  cases,  which,  once  established, 
are  so  intractable  to  treatment. 

To  the  clinician  who  is  satisfied  with  his  present  method  of  treat- 


152  PROTEIN  THERAPY 

ment  of  acute  articular  rheumatism,  or  of  chronic  arthritis,  nonspe- 
cific therapy  naturally  has  nothing  to  offer.  To  those  of  us  who 
are  not  so  satisfied  I  believe  it  adds  a  definitely  useful  agent  and  at 
times  a  very  powerful  one.  Indeed  to  those  who  are  interested  in 
nonspecific  therapy  or  the  mechanism  involved,  the  arthritic  cases 
offer  a  particularly  valuable  field  for  research.  There  is  practically 
no  risk  to  the  patient — as  there  might  be  in  more  or  less  experi- 
mental work  on  the  more  acutely  ill — the  signs  of  improvement  or 
retrogression  are  objectively  under  the  control  of  the  physician  and 
the  interesting  focal  reaction  elicited  by  the  nonspecific  agents  at 
the  inflammatory  site  can  be  carefully  observed,  especially  in  the 
more  chronic  type  of  arthritis. 

The  mechanism  that  is  involved  in  the  recovery  of  the  patient  is 
still  quite  obscure.  It  is  to  be  taken  for  granted  that  we  must  first 
of  all  seek  to  remove  any  apparent  focus  of  infection.  Whether 
the  joint  pathology  always  represents  actual  bacterial  invasion  or 
at  times  merely  a  focal  reaction  of  hypersensitive  tissues  is  by  no 
means  a  settled  question.  We  do  know  that  the  nonspecific  injection 
brings  about  a  focal  reaction  and  that  the  mechanism  of  recovery 
Linges  on  this  reaction.  Whether,  as  a  result  of  the  reaction  the 
local  tissues  become  immune  to  the  toxic  effect  of  bacteria  still  alive 
in  the  focus,  whether  it  means  merely  an  increased  tolerance  to  toxic 
split  products  set  free  at  a  distance  and  to  which  the  local  tissues  had 
heretofore  been  sensitive,  or  whether  we  deal  with  the  actual  de- 
struction of  bacteria  which  had  become  localized  in  the  joint  is  not 
determined.  We  can  simply  point  to  the  analogy  that  exists  between 
the  skin  and  the  joint  tissues  in  their  property  of  distinct  local  sensi- 
tization,  and  to  the  fact  that  the  reaction,  being  a  focal  one  (a  Herd 
reaktion),  can  be  brought  about  by  a  great  variety  of  agents  and 
metabolic  alterations  (the  recent  paper  of  Gaisbeck  on  acute  arthritis 
and  hemiplegia  is  of  interest  in  this  connection) ;  and  as  such  is  typical 
in  its  manifestations  both  in  the  negative  phase  (increased  inflamma- 
tion) and  the  positive  phase  (decreased  inflammation).  For  the 
therapist  it  is  the  latter  that  is  of  greatest  interest. 


CHAPTER  IX 
THE  TREATMENT  OF  TYPHOID  AND  PARATYPHOID  FEVER 

Investigations  in  the  treatment  of  typhoid  fever  formed  the  basis 
upon  which  our  modern  conception  of  the  nonspecific  factors  in 
therapy  are  based,  not  only  in  the  very  recent  contributions  to  the 
literature,  but  in  the  older  work  such  as  that  of  Rumpf. 

Typhoid  Vaccine. — In  the  decade  preceding  the  war  the  thera- 
peutic use  of  typhoid  vaccines  in  typhoid  fever  had  been  developed 
particularly  by  French  scientists  (Chantemesse  and  Widal,  Vincent, 
etc.)  and  a  number  of  vaccines  were  elaborated  by  them,  each  with 
some  supposed  point  of  superiority.  The  sensitized  vaccine  of 
Besredka  had  been  used  with  a  measure  of  success.  Stern  many 
years  ago  had  suggested  the  use  of  an  antitoxic  agent,  while  the 
use  of  convalescent  serum  was  introduced  by  Hammerschlag  and 
used  also  by  Konigsfeld,  von  Jaksch  and  Pollak.  A  comprehensive 
review  of  this  period  and  of  vaccine  therapy  in  typhoid  fever  in 
general  will  be  found  in  Gay's  monograph,  as  well  as  in  the  report 
of  Krumbhaar  and  Richardson.  The  latter  reached  the  conclusion 
that  the  larger  the  dose  of  vaccine,  the  better  the  therapeutic  result. 
But  large  doses  of  vaccine  were  not  in  vogue;  one  hesitated  in  giving 
large  reactive  doses  in  chronic  diseases  where  there  was  little  risk; 
naturally  enough  this  caution  was  more  than  observed  in  such  an 
acute  condition  as  typhoid  fever  where  logically  it  would  seem  to  be 
decidedly  unwarranted  to  add  more  toxin  to  an  already  overburdened 
organism. 

Intravenous  Injections. — From  two  quite  independent  sources, 
however,  this  established  view  was  rather  abruptly  overthrown.  In 
Argentine  a  group  of  clinicians  found  that  if  they  injected  typhoid 
vaccine  intravenously  during  the  course  of  typhoid  fever  certain 
remarkable  critical  terminations  of  the  disease  were  to  be  observed; 
in  other  cases  the  disease  terminated  by  lysis  shortly  after  the  injec- 
tion; even  those  that  were  not  affected  in  so  far  as  the  temperature 
course  was  concerned  seemed  much  less  toxic  than  before  the  injection. 
This  work,  carried  out  by  Penna,  Torres,  Dessy,  Grafiolo,  Fossati  and 
others,  formed  the  basis  on  which  Kraus  later  began  his  work  with 
heterovaccination  in  typhoid  fever. 

At  about  the  same  time  Ichikawa  published  a  series  of  cases  of 
typhoid  fever  treated  with  intravenous  injections  of  typhoid  vaccine 
with  similarly  striking  results.  He  used  a  sensitized  vaccine  for  the 

153 


154  PROTEIN  THERAPY 

purpose,  made  up  as  follows:  10  loops  of  fresh  typhoid  culture  were 
suspended  in  10  c.c.  of  human  typhoid  convalescent  serum  and  in- 
cubated for  5  or  6  hours.  The  organisms  were  then  centrifuged  from 
the  serum,  washed  three  times  in  physiological  salt  solution,  suspended 
in  100  c.c.  of  physiological  salt  solution  with  0.3%  phenol  and  finally 
shaken  for  1  hour.  The  vaccine  was  not  heated.  Of  this  emulsion 
0.5  c.c.  was  diluted  in  a  syringeful  of  saline  before  injection  and  the 
whole  slowly  injected  intravenously. 

In  most  of  Ichikawa 's  cases  a  single  injection  sufficed  to  terminate 
the  febrile  course  of  the  disease;  in  some  the  result  was  not  quite  so 
marked.  After  the  critical  drop  in  the  temperature  the  temperature 
would  again  rise  in  these  cases,  usually  remaining  intermittent  in  type 
and  much  lower  than  before.  The  general  condition  of  these  latter  pa- 
tients was  always  much  better  after  than  before  the  injection.  In  the 
refractory  cases  the  injection  was  usually  repeated  once  and  even  twice 
until  the  desired  result  was  obtained. 

Ichikawa  assumed  that  the  effect  on  the  temperature  curve  was 
due  to  a  mobilization  of  antibodies  that  had  been  formed  in  the  cells 
during  the  course  of  the  infection  but  had  not  been  thrown  into  the 
general  circulation  until  the  vaccine  was  injected  intravenously. 

The  mortality  in  this  first  series  was  11%,  rather  high  in  itself, 
but  not  in  comparison  to  the  death  rate  in  untreated  cases  in  the  Osaka 
Hospital,  which  was  around  30%. 

Ichikawa  did  not  observe  any  ill  effects  from  the  vaccine  injec- 
tion; indeed  he  considers  it  unjustifiable  to  neglect  the  advantages 
of  intravenous  therapy  merely  because  certain  inherent  dangers  are, 
theoretically,  to  be  considered.  He  watched  particularly  for  cardio- 
vascular changes  but  did  not  have  any  collapse  cases,  and  hemorrhages 
were  less  frequent  in  his  vaccinated  cases  than  in  the  untreated.  In 
a  few  cases  he  did  observe  hemorrhages  from  1  to  3  days  after  the 
injections;  usually  they  were  slight  and  not  alarming  in  character. 
In  two  cases  he  observed  hemoptysis,  twice  nose-bleeding,  and  in  two 
cases  hemorrhages  into  the  skin,  but  they  were  all  mild  in  character 
and  did  not  recur.  The  reaction  that  occurred — chill,  fever  to  40° 
C.,  relatively  high  pulse,  occasional  nausea,  dyspnea,  etc. — was 
transient;  even  the  increased  temperature  never  persisted  over  24 
hours. 

Hetero vaccines. — Kraus  and  Mazza  reported  their  work  in  1914 
in  which  not  only  the  results  obtained  with  intravenous  injection  of 
typhoid  vaccine  in  typhoid  fever  was  described,  but  the  use  of  hetero- 
vaccines  was  taken  up.  Ichikawa  had  previously  noticed  that  with 
typhoid  vaccine  he  could  treat  paratyphoid  fever  just  as  well  as 
typhoid.  Kraus  and  Mazza  found  that  colon  vaccine  did  just  as 
well,  and  besides  reported  on  the  effect  of  the  intravenous  injection 
of  such  vaccines  in  puerperal  infection,  where  relatively  long  stand- 
ing infections  were  promptly  terminated  and  the  disease  process 


TYPHOID  AND  PARATYPHOID  FEVER  155 

cured.  Kraus  suggested  the  extension  of  the  method  of  treatment 
to  a  number  of  diseases  such  as  scarlet  fever,  plague,  septicemia,  etc. 
Other  reports  were  soon  published  dealing  with  nonspecific  therapy 
in  typhoid  fever;  most  of  the  observers  first  used  typhoid  vaccine. 
Thus  Rhein  tried  it  in  33  cases.  He  prepared  his  vaccine  as  follows: 
To  5  c.c.  of  Halle  typhoid  vaccine  and  0.5  gm.  pure  phenol,  physio- 
logical salt  solution  was  added  to  a  volume  of  100  c.c.  Of  this  prepa- 
ration he  employed  0.6  to  1.4  c.c.  diluted  with  8  c.c.  physiological 
salt  solution  for  intravenous  injection.  Within  one  to  two  and  a 
half  hours  a  rise  in  temperature  and  a  chill  of  varying  severity  and 
duration  (five  to  thirty  minutes)  occurred  in  94  per  cent,  of  the 
cases.  Injections  were  made  only  in  patients  in  whom  the  diagnosis 
was  clear  clinically  or  bacteriologically.  Three  of  the  patients  treated 
showed  paratyphoid  bacilli  A  in  the  blood.  Patients  exhibiting  the 
steplike  curve  of  defervescence  were  excluded,  as  were  also  those 
suffering  with  complications  such  as  pneumonia,  pleurisy,  nephritis, 
or  myocarditis.  Status  typhosus,  with  delirium  and  bronchitis,  but 
with  good  pulse,  was  not  looked  upon  as  contra-indication  for  injec- 
tion of  vaccine.  Thirty -three  patients  received  the  injections  and 
6  of  these  had  a  second  injection.  In  9  cases  there  was  a  critical 
fall  of  temperature  within  one  day  after  the  first  injection  and  in 
1  case  after  the  second.  In  13  cases  a  favorable  effect  on  the  tem- 
perature curve  was  noted  after  the  first  injection  and  in  3  cases  after 
the  second  injection.  In  8  patients  there  was  no  effort  whatever  on 
the  temperature  curve,  and  in  2  of  these  a  second  injection  was  also 
without  visible  effect.  On  the  other  hand,  3  patients  who  were  un- 
affected by  the  first  injection  reacted  favorably  after  the  second. 
In  the  3  cases  of  paratyphoid  fever  a  critical  fall  of  temperature  was 
not  observed,  but  there  was  a  gradual  lowering  in  the  fever.  Of 
the  patients  injected,  3  died;  in  none  could  the  death  be  attributed 
to  the  injection.  Of  all  the  patients  treated,  only  1  suffered  from 
intestinal  hemorrhage,  which  occurred  six  days  after  the  injection. 
Other  complications  were  not  observed  in  the  injected  patients.  No 
evidence  of  collapse  even  in  patients  with  weak  pulse  was  seen.  The 
reaction  of  the  patient  to  the  injection  was  studied  with  relation  to 
the  following  clinical  signs  or  symptoms:  Bronchitis,  palpable  spleen, 
roseola,  diazo-reaction,  leukocyte  count,  eosinophil  count,  and  bac- 
teriemia.  A  favorable  response  to  the  injection  could  not  be  corre- 
lated with  any  of  these.  However,  after  crisis,  comparatively  many 
eosinophils  (100  to  200  per  c.mm.)  appeared  in  the  blood  in  twenty- 
four  hours  in  spite  of  the  leukopenia,  and  the  diazo  test  remained 
positive  as  long  as  three  days  after  the  temperature  was  normal.  It 
was  noticeable  that  with  larger  dosage  (4  c.c.)  the  crisis  was  of 
shorter  duration.  Since  no  ill  effects  followed  the  injection,  and,  on 
the  contrary,  in  48  per  cent,  of  the  cases  the  fever  was  shortened 
and  in  30  per  cent,  cure  followed  within  two  days,  Rhein  believed 


156  PROTEIN  THERAPY 

that  in  every  case  of  uncomplicated  typhoid  fever,  bacteriotherapy 
should  be  tried. 

Biedl  and  Eggreth  also  gave  their  experiences  with  the  vaccine 
treatment  of  typhoid  fever.  Biedl  treated  a  series  of  22  cases  of 
severe  typhoid  fever  in  the  beginning  of  the  second  week;  the 
blood  culture  was  positive  in  all  of  these.  Of  this  number  2  are 
excluded.  Both  were  men  with  high  fever,  status  typhosus,  and 
recurring  epistaxis,  the  last  nose-bleed  occurring  one  day  before  in 
each  case.  Two  hours  after  injection  of  the  vaccine  there  occurred 
in  each  patient  an  uncontrollable  hemorrhage  from  the  nose  which 
led  to  death.  Of  the  remaining  20  cases,  11  received  Vincent's  vac- 
cine (typhoid  bacilli  killed  with  ether),  first  100  million,  later  250 
million  to  300  million  in  2  c.c.  of  salt  solution,  and  9  were  treated 
with  Besredka's  vaccine  intravenously  (sensitized  living  typhoid 
bacilli)  in  doses  of  250  million  to  300  million  in  2  c.c.  of  salt  solu- 
tion. The  end  result  was  as  follows:  Of  the  cases  treated  with  Vin- 
cent's vaccine  3  died;  2  received  subcutaneous  injections  and  died 
fourteen  and  eighteen  days  respectively  after  the  injection;  1  treated 
intravenously,  after  an  initial  favorable  response,  died  in  the  third 
week  from  severe  bronchopneumonia  and  heart  weakness.  Evi- 
dently none  of  these  deaths  were  due  to  the  vaccine.  The  remaining 
8  patients  recovered.  All  of  the  patients  treated  with  Besredka's 
vaccine  recovered.  Biedl's  impressions  were  decidedly  favorable. 
After  intravenous  injection  the  temperature  rose  in  one  to  two  or  three 
hours  from  39°  to  40°  C.  (102.2°  to  104°  F.),  in  one  case  even  to  42° 
C.  (107.6°  F.),  followed  in  twelve  to  eighteen  hours  by  a  critical  fall  of 
temperature  to  normal.  No  signs  of  collapse  were  observed;  indeed, 
in  two  cases  the  injection  was  made  when  the  patients  were  in  a  state 
of  collapse  with  a  pulse  which  could  not  be  counted.  Within  three 
hours  the  temperature  rose,  the  pulse  became  much  fuller  with  a  rate 
of  100  per  minute.  Following  crisis  the  patients  felt  much  better.  The 
patients  treated  with  Besredka's  vaccine  remained  afebrile.  Some  of 
the  other  patients  had  slight  evening  elevations  of  temperature;  in 
none  above  38°  C.  (100.4°  F.).  Eggreth  treated  a  series  of  43  cases  of 
typhoid  with  a  single  intravenous  injection  of  0.5  to  1.0  c.c.  of  Bes- 
redka's vaccine.  Subcutaneous  injections  had  produced  no  result. 
In  34  cases  of  Eggreth's  series  a  critical  fall  of  temperature  followed 
within  three  to  twelve  hours  after  the  injection,  frequently  with  pro- 
fuse sweating  and  marked  relief  of  headache  and  delirium.  Of  these 
patients  31  remained  afebrile;  the  remaining  3  developed  fever  after 
twelve,  fourteen,  and  fifteen  days,  due  respectively  to  endocarditis, 
to  bilateral  purulent  parotitis,  and  to  suppurative  osteoperiostitis. 
The  majority  of  the  patients  received  the  injection  between  the  sev- 
enth and  sixteenth  day  of  the  disease.  In  a  group  of  8  cases  in  the 
fourth  and  fifth  week  of  the  disease,  suffering  with  broncho-  or  pleuro- 
pneumonia,  the  injection  was  ineffective.  The  forty -third  case  died 


TYPHOID  AND  PARATYPHOID  FEVER  157 

three  hours  after  the  injection.  An  autopsy  was  performed  which 
revealed  typical  typhoid  lesions  in  the  small  intestine,  pneumonia,  and 
myocarditis.  The  patient  had  been  brought  to  the  hospital  uncon- 
scious and  desperately  ill,  and  a  poor  risk.  Paltauf,  at  whose  re- 
quest Biedl  and  Eggreth  had  reported  their  experiences  from  the 
military  hospitals,  uttered  a  word  of  warning,  as  he  had  heard  of 
a  few  instances  of  collapse  following  the  intravenous  use  of  Bes- 
redka's  vaccine. 

In  the  earlier  experience  collapse  and  even  death  after  the  intra- 
venous injection  of  relatively  large  doses  of  typhoid  and  other  toxic 
vaccines  was  not  uncommon  (Kraus  and  Mazza,  Boral,  v.  Reuss)  and 
the  caution  expressed  by  Paltauf  is  more  than  justified.  The  early 
doses  were  tremendous  and  would  put  even  a  healthy  individual  to 
considerable  strain;  that  patients  severely  ill  would  occasionally  suc- 
cumb to  the  treatment  was  therefore  not  unexpected. 

At  a  meeting  of  the  Gesellschaft  fur  Aerzte  in  Wien  (June  18, 
1915)  a  number  of  clinical  reports  were  presented  which  are  of  in- 
terest. Nobel  treated  14  cases  of  typhoid  with  intravenous  typhoid 
vaccine  injections.  Of  these  11  were  cured  after  one  injection,  3 
died.  Zupnik,  who  used  typhoid,  meningococcus  and  albumose  in- 
jections, brought  out  the  fact  that  small  doses  were  much  prefer- 
able to  the  larger  ones  heretofore  used,  because  the  therapeutic  re- 
sult was  just  as  good  and  the  danger  to  the  patient  much  less.  Fleck- 
seder  treated  41  cases  of  typhoid  with  intravenous  injections  of  Bes- 
redka  vaccine.  Of  these  21  cases  proved  refractory.  In  20  cases 
the  temperature  came  down  after  several  injections.  He  used  fairly 
large  doses  and  saw  several  cases  of  vasomotor  collapse.  In  two 
cases  a  hemorrhagic  nephritis  developed.  He  therefore  considered  the 
treatment  of  doubtful  value,  particularly  in  severe  cases.  Stoerk 
used  albumoses  and  obtained  results  that  were  similar  to  those  ob- 
tained with  typhoid  vaccine. 

Meyer  reported  a  series  of  cases  treated  with  typhoid  vaccine 
with  typical  results  but  in  a  later  discussion  is  rather  inclined  to  think 
that  the  intravenous  injection  of  typhoid  vaccine  is  too  strenuous. 
He  has  come  to  the  conclusion  that  some  of  the  milder  agents  will  be 
found  much  more  satisfactory  for  general  use.  Lucksch  has  reached 
the  same  conclusion.  Other  earlier  reports  are  those  of  v.  Czylharz, 
v.  Czylharz  and  Neustadtl,  Neustadtl,  Reibmayr  and  Decastello, 
Sladek  and  Kotlowsky. 

Reibmayr  and  also  Decastello  reported  on  a  series  of  cases 
treated  with  cholera  and  colon  vaccines.  In  Decastello's  cases  he 
injected  30  million  organisms  (colon)  which  gave  a  sharp  reaction. 
In  10  cases  of  typhoid  fever  4  responded  by  defervescence  by  crisis, 
1  by  lysis  after  the  first  injection.  Three  more  cases  became  normal 
by  lysis  after  the  third  injection;  in  two  cases  there  was  no  effect 


158  PROTEIN  THERAPY 

to  be  observed  on  the  course  of  the  disease  following  the  injection. 

Thus  heterovaccine  therapy  was,  clinically  at  least,  definitely  es- 
tablished and  has  come  to  be  accepted  even  when  the  vaccine  is 
used  subcutaneously.  Stein  in  presenting  the  results  on  about  1,500 
cases  of  typhoid  treated  by  him  both  subcutaneously  and  intrave- 
nously found  that  by  either  method  of  administration  colon  vaccine 
would  give  comparable  results. 

The  theory  could  still  be  advanced  that  the  vaccines  injected  were 
more  or  less  related  biologically  and  that  group  reactions  might  im- 
munologically  account  for  the  result,  an  idea  that  Ichikawa  had  ad- 
vanced to  account  for  the  success  of  the  typhoid  vaccine  in  para- 
typhoid fever. 

Milk  and  Albumoses. — Even  this  last  resource  of  our  older  concep- 
tion was  swept  away  with  the  demonstration  of  the  fact  that  typhoid 
fever  could  be  treated  with  equally  good  clinical  results  with  intra- 
muscular injections  of  milk  or  intravenous  injections  of  protein 
products. 

Liidke  in  1915  reported  on  23  cases  of  typhoid  fever  treated  with 
intravenous  injections  of  deutero-albumose  and  later  reported  on  a 
series  of  78  cases  of  typhoid  fever  and  paratyphoid  B  fever  with 
the  following  results: 

In  26  cases  there  was  a  complete,  critical  defervescence. 

In  10  cases  there  was  a  complete  defervescence  in  from  3  to  5  days. 

In  31  cases  the  temperature  came  to  normal  in  from  7  to  12  days, 
while  in  11  cases  there  was  no  appreciable  effect  on  the  temperature 
curve. 

The  deutero-albumose  used  by  Liidke  contained  about  15%  of  salt 
as  well  as  some  protalbumose  and  was  used  in  the  majority  of  cases 
in  10%  solution.  In  the  normal  individual  the  injection  of  1  to  1% 
c.c.  of  this  solution  caused  no  reaction.  (In  one  normal  individual 
a  second  injection  given  after  an  interval  of  two  weeks  produced  a 
slight  chill  and  a  rise  in  temperature  that  persisted  for  about  4  hours.) 

Liidke  has  never  seen  an  unfavorable  effect  on  the  pulse  follow- 
ing proteose  injections  in  any  acute  infection.  There  were  no  deaths 
in  these  78  cases  of  typhoid  or  paratyphoid  fever.  The  average  dura- 
tion of  the  disease  in  these  cases  was  from  one  to  two  weeks  and  he  has 
noted,  as  others  have  constantly  reported,  that  the  earlier  the  treat- 
ment is  inaugurated,  the  better  the  results. 

Perhaps  the  largest  series  treated  with  deutero-albumoses  is  that 
of  Holler  (350  cases).  His  method  of  injection  differed  materially 
from  those  heretofore  employed  in  that  he  gave  daily  injections, 
usually  commencing  with  1  c.c.  of  a  10%  solution  and  increasing 
the  dose  about  0.5  c.c.  with  each  injection,  depending  of  course 
on  the  reaction.  His  cases  were  all  kept  on  a  fluid  diet,  were  given 
charcoal  as  well  as  urotropin,  but  otherwise  had  no  medication  apart 


TYPHOID  AND  PARATYPHOID  FEVER  159 

from  the  proteose  injections.  His  mortality  was  only  %  per  cent.; 
he  experienced  no  prostration  or  hemorrhage  of  moment  in  the  en- 
tire series.  The  average  duration  of  the  disease  was  10  days.  Nat- 
urally the  earlier  the  cases  came  to  treatment,  the  more  apparent 
and  satisfactory  were  the  results.  During  the  course  of  his  experi- 
ence he  used  ovalbumin,  adrenalin,  typhoid  convalescent  serum,  horse 
serum  and  pleural  exudate  intravenously,  but  for  general  use  he  ob- 
tained the  most  satisfactory  results  with  the  proteose. 

Jobling  and  the  writer  treated  a  series  of  typhoid  cases  with  a 
secondary  proteose  preparation,  some  of  which  were  reported  in  a  pa- 
per published  in  1916,  and  Miller  and  Lusk,  and  Miller  reported  on 
the  treatment  of  typhoid  fever  both  with  typhoid  vaccine,  with  prote- 
oses  and  with  pollen  extract.  Nolf  has  also  used  peptone  in  typhoid 
fever  with  satisfactory  results. 

In  1916  Schmidt,  Luithlen,  Saxl,  Bruck  and  Kiralihyda,  Miiller 
and  Weiss,  introduced  intramuscular  milk  injections.  Two  factors 
tended  to  popularize  this  agent — the  relative  ease  of  administration 
(intravenous  injections  being  at  times  more  or  less  formidable)  and 
the  availability  of  milk — so  that  for  the  past  three  years  one  finds 
perhaps  most  of  the  reports  on  the  effects  of  nonspecific  therapy  based 
on  experience  gained  with  milk  injections.  Saxl,  Bruck  and  Kirali- 
hyda at  first  reported  on  the  use  of  milk  on  gonorrheal  complica- 
tions, but  Saxl  shortly  reported  on  26  cases  of  typhoid  fever  treated 
with  injections  of  this  kind.  In  almost  all  cases,  after  an  initial 
temperature  increase  that  persisted  for  about  two  days,  the  tempera- 
ture came  to  a  normal  level  by  lysis.  Corinaldesi  gave  intravenous 
injections  of  1  c.c.  of  a  2  or  4  per  cent,  solution  of  deutero-albumose 
in  a  case  of  typhoid  and  one  of  paratyphoid,  according  to  Liidke's 
technic.  No  benefit  was  apparent.  Then  he  tried  intramuscular  in- 
jections of  5  or  10  c.c.  of  sterilized  milk  in  five  patients  with  lobar 
or  bronchopneumonia  or  typhoid  and  was  astonished  at  the  prompt 
and  permanent  improvement  that  followed  one,  two  or  three  injec- 
tions, without  disturbances  or  much  local  reaction.  There  was  only 
rarely  a  slight  chill  and  it  was  mild.  His  findings  thus  confirm  the 
way  in  which  parenteral  introduction  of  some  protein  substance  is 
able  to  stimulate  the  defensive  forces  and  aid  in  the  throwing  off  of  the 
disease,  irrespective  of  the  nature  of  the  protein  injected. 

Galambos  made  an  effort  to  determine  which  of  these  agents 
so  far  described  might  be  of  greatest  value.  In  a  series  of  136  cases 
he  used  deutero-albumose,  vaccines  (colon,  gonococcus  and  staphylo- 
coccus)  and  salt  solution.  In  25  cases  treated  with  injections  of  1  c.c. 
of  a  4%  solution  of  deutero-albumose  he  obtained  a  critical  drop  in 
the  temperature  in  50%  of  the  cases.  Vaccines  seemed  much  less 
effective;  more  and  repeated  injections  had  to  be  given  in  order  to 
obtain  the  same  result.  The  dosage  varied,  about  25  million  of  colon 


160  PROTEIN  THERAPY 

and  gonococcus  organisms  were  injected,  250  million  of  the  staphylo- 
coccus,  in  order  to  obtain  a  satisfactory  reaction. 

When  100  c.c.  of  physiological  salt  solution  was  injected  a  defer- 
vescence was  obtained  in  70%  of  the  cases. 

In  the  total  series  the  mortality  was  6%  and  the  results  can  be 
summarized  as  follows: 

Critical  defervescence 22% 

Prompt  lysis 22% 

Marked   improvement    18% 

Moderate  improvement    9% 

No  effect   28% 

As  a  result  of  his  investigation  Galambos  inclined  to  the  treat- 
ment with  protein  split  products. 

The  treatment  by  salt  solution  injections  was  first  reported  by 
Englander.  Englander  while  treating  a  bleeding  typhoid  case  injected 
about  300  c.c.  of  salt  solution  intravenously  and  found  that  this  was 
followed  by  a  typical  chill  and  a  defervescence  the  following  day. 
Mitlander  later  reported  on  the  same  method. 

Comparative  Results. — Galambos — who  studied  the  intravenous 
therapy  of  typhoid  and  paratyphoid  fevers  with  Besredka's  vaccine  and 
with  albumose,  hetero vaccines  and  salt  solution,  as  just  mentioned — 
reported  later  on  the  treatment  of  120  cases  with  methylene  blue. 

He  considers  intravenous  treatment  limited  in  its  application  for  sev- 
eral reasons:  it  requires  a  certain  degree  of  skill  and  experience  on  the 
part  of  the  physician,  who  must  rule  out  contra-indicated  cases — myo- 
carditis, pneumonic  complications,  etc.;  there  are  associated  with  the  in- 
jections certain  dangers  of  hemorrhage  and  of  collapse  (from  1%  to  2%) ; 
the  substances  used  are  not  chemically  defined  and  experience  must  be 
gained  with  the  dosage  before  one  can  be  fairly  safe  in  using  the  method. 
This  came  to  Galambos'  attention  when  he  reviewed  his  earlier  and  his 
later  results  with  nonspecific  therapy.  In  his  last  50  cases  where  he  used 
only  a  small  dose  of  Besredka  vaccine  intravenously  (}4  c.c.)  he  had  no 
hemorrhage  or  collapse  at  all,  and  he  likewise  had  no  ill  effects  in  his 
series  of  60  cases  treated  with  albumoses.  The  intravenous  injection  of 
larger  amounts  of  salt  solution  was  found  too  cumbersome  for  routine 
use. 

To  overcome  some  of  these  practical  objections  he  began  the  use  of 
methylene  blue,  which,  being  a  chemically  defined  substance,  could  be 
standardized,  and  while,  being  a  protoplasmic  stimulant  as  the  others,  could 
be  given  by  mouth  without  a  marked  reaction.  He  gave  1.2  gm.  per  day 
in  doses  of  20  cgm.  every  4  hours.  The  effect  on  the  temperature  was 
usually  apparent  in  a  few  days,  usually  declining  by  lysis.  The  euphoria 
so  commonly  observed  in  nonspecific  therapy  was  apparent  in  most  in- 
stances. The  medication  was  continued  some  days  after  the  temperature 
reached  normal.  If  discontinued  too  early  an  occasional  recrudescence 
was  noted. 


TYPHOID  AND  PARATYPHOID  FEVER  161 

In  120  cases  so  treated  the  severity  of  the  disease  was  roughly  as  fol- 
lows (50  cases  of  mild  disease  were  not  treated  at  all) : 

63  moderately  severe;  typhoid  2 ;  Para  "A"  35 ;  Para  "B"  4 ;  undetermined  22 

23  severe;  "       5;     "  11;     "  1;  "  6 

9  very  severe;  "       2;     "  4;     "  1;  "  2 

Of  the  typhoid  cases  many  had  had  a  prophylactic  injection  shortly 
before  their  admission  to  the  ward.  (There  was  probably  no  vaccination 
against  paratyphoid,  although  it  is  not  specifically  stated  in  Galambos' 
paper.) 

The  results  of  the  methylene  blue  therapy  was  as  follows : 

In  13%  lysis  set  in  immediately  after  the  treatment. 
26%  lysis  somewhat  more  delayed. 

13%  favorably  influenced,  but  not  much  effect  on  temperature. 
44.6%  not  influenced. 
3.4%  died. 

Compared  to  the  results  with  the  vaccine  therapy  before  used  the  mor- 
tality was  somewhat  less  but  the  general  effect  on  either  critical  or  lytic 
termination  of  the  disease  not  so  apparent. 

When  one  comes  to  study  the  comparative  value  of  the  intravenous 
method  of  therapy  as  contrasted  with  the  subcutaneous  injection  of 
vaccine  in  the  treatment  of  typhoid  fever,  the  statistics  of  Barrenscheen 
are  of  value. 

Barrenscheen  treated  over  200  cases  of  typhoid,  using  Besredka's  vaccine 
intravenously  as  well  as  subcutaneously;  a  small  series  was  also  treated 
with  the  Vincent  vaccine  subcutaneously. 

Unfavor- 

Cured        ably  Infl.        Not  Infl.          Died 
Besredka     Intravenously 

136  cases 87  =  63%     5  =  3.6%       34  =  25%    10  =  7.35% 

Besredka  Subcutaneously 

52  cases 26  =  50%     3  =  5.7%       17  =  32%      6  =  11% 

Vincent    Subcutaneously 

19  cases 4  =  21%     3  =  15%        12  =  63%       0  =  0 

The  intravenous  dose  was  100  million  (sensitized  vaccine)  and  if  the 
patient  was  not  afebrile  after  the  first  injection  a  second  dose  was  given 
after  two  or  three  days;  no  more  than  three  doses  were  given,  because 
Barrenscheen  found  that  if  the  patient  was  refractory  it  was  useless  to 
continue.  In  30%  of  the  cases  a  critical  termination  of  the  disease  was 
obtained  after  a  single  injection. 

For  subcutaneous  injection  he  used  500  million  organisms,  followed 
two  days  later  by  1,000  million  if  there  had  been  no  effect  on  the  temper- 
ature. This  dose  was  increased  somewhat  for  the  third  injection  but  he 
never  gave  more  than  a  total  of  9,000  million  organisms  during  the  entire 
course  of  the  treatment. 

As  a  result  of  his  experience  Barrenscheen  considers,  as  other  observers 


162  PROTEIN  THERAPY 

also  do,  that  the  first  week  or  ten  days  of  the  illness  offers  the  best  time 
for  treatment;  after  the  third  week  he  considers  it  not  only  valueless  but 
dangerous  (because  of  the  danger  of  hemorrhage  or  perforation). 

He  does  not  give  it  in  any  cases  where  the  pulse  is  over  100,  where 
there  is  any  evidence  of  lung  complication  or  where  a  tendency  to  hemor- 
rhage is  present — nose-bleeding,  blood  in  stool,  etc.  If  these  conditions 
are  observed  the  mortality  would  be  even  lower  than  that  obtained  in  his 
series,  for  many  of  his  results  that  were  unsatisfactory  were  the  result  of 
his  earlier  efforts  when  he  was  not  sufficiently  experienced.  In  only  one 
case  did  he  find  that  death  was  due  to  a  complication  resulting  directly 
from  the  injection.  This  was  a  perforation  that  came  to  notice  immediately 
after  the  injection. 

In  four  cases  a  rather  widespread  roseola  was  observed  shortly  after 
the  injection.  It  had  no  further  significance  but  might  disturb  an  inex- 
perienced clinician. 

The  intravenous  injection  seemed  much  superior  to  the  subcutaneous, 
not  only  apparent  in  the  statistical  result  but  because  of  the  prompt  bet- 
tering of  the  general  condition  of  the  patient.  Headache  and  insomnia 
disappeared,  the  appetite  improved  and  the  mental  conditions  always  cleared 
up.  On  the  other  hand  this  effect  was  never  so  apparent  after  the  subcu- 
taneous injections  and  there  seemed  no  doubt  in  his  mind  that  the  effect 
of  the  subcutaneous  dosage  was  bad  on  the  pulse.  Both  after  the  Besredka, 
more  frequently  after  the  Vincent  vaccine  the  ill  effect  on  the  pulse  was 
observed  and  in  some  instances  stimulants  had  to  be  generously  used  before 
the  equilibrium  was  restored. 

Following  the  intravenous  injections  the  usual  reaction  was  observed, 
with  temperature  reactions  from  40°  to  41°  C.  (104°  to  105.8°  F.),  in  one 
instance  to  41.9°  C.  (106.3°  F.).  The  pulse  never  went  over  120  and 
always  remained  of  good  quality  and  the  patient  without  evidence  of  cardiac 
impairment — there  was  no  dyspnea,  cyanosis,  etc.  After  the  second  injec- 
tion the  temperature  response  was  not  as  high  as  with  the  first,  nor  was 
the  leukocyte  count  altered  as  much. 

During  convalescence  the  patient  should  be  kept  rigidly  in  bed,  at  least 
for  a  week  after  the  temperature  has  been  normal,  and  careful  attention 
given  the  diet  and  the  bowels.  In  several  cases  where  the  patient  became 
constipated  a  temperature  reaction  was  observed  which  lasted  several  days. 
Occasionally  a  pronounced  bradycardia  was  found  during  convalescence. 
Pulse  counts  as  low  as  36  to  50  were  not  uncommon  in  these  cases,  while 
an  arrhythmia  was  at  times  present.  Barrenscheen  is  under  the  impression 
that  no  myocarditis  was  present  in  his  cases,  but  the  fact  that  he  lost  two 
cases  who  got  up  and  walked  around  two  days  after  their  recovery  by  crisis 
might  lead  one  to  think  otherwise. 

Grote  treated  24  cases  of  typhoid  with  milk  injections  with  good 
results  but  came  to  the  conclusion  that  the  injections  must  be  given 
early  if  they  are  to  be  effective. 

Mark  White  has  reported  on  the  treatment  with  normal  horse 
serum;  E.  F.  Muller  on  the  use  of  casein  injections,  both  with  favor- 
able results.  Ullmann  treated  typhoid  with  "Dispargin,"  a  silver 
colloid;  Salomon  has  reported  favorable  results  in  141  cases  treated 


TYPHOID  AND  PARATYPHOID  FEVER      163 

with  a  colloidal  gold  preparation  and  Labbe  and  Moussaud  have  also 
made  use  of  the  latter  agent. 

Svestka  and  Marek  used  "Typhin,"  the  nucleohiston  prepared 
from  typhoid  bacilli.  In  60  cases  so  treated  they  grouped  the  clini- 
cal results  as  follows:  In  one  case  the  temperature  increased  for 
the  day  following  the  injection,  then  fell  and  remained  normal.  In 
14  cases  remissions  began,  the  temperature  coming  down  with  the, 
usual  remissions  normally  observed  in  the  late  stages  of  typhoid. 
In  the  balance  of  the  cases  the  remissions  became  greater  but  the 
disease  continued  the  usual  length  of  time.  In  21  cases  2  injections 
were  made;  in  11,  3  injections.  They  observed  no  increase  in  the 
agglutinin  titer  of  the  serum  after  the  injections. 

Neustadt  and  Marcovici  treated  25  cases  of  typhoid  with  "Typhin" 
and  as  a  routine  measure  gave  digitalin  2  days  before  the  injection  to 
counteract  any  tendency  of  collapse  on  the  part  of  the  vascular  sys- 
tem. In  21  cases  the  injection  was  made  intravenously.  In  11  of 
these  cases  there  was  apparent  a  decided  influence  on  the  disease 
process — in  5  of  these  11  the  fever  terminated  by  crisis;  4  cases  gave 
evidence  of  some  alteration  and  apparent  shortening  of  the  course 
of  the  disease;  3  cases  were  much  less  toxic  after  the  injections;  3 
patients  died,  one  in  collapse.  Of  four  cases  injected  intramuscularly, 
2  were  influenced  favorably,  but  the  effect  was  not  as  marked  as  with 
the  intravenous  injections. 

Svestka  and  Marek  consider  that  the  method  can  be  used  with- 
out harm  to  the  patient  and  is  of  decided  value  when  given  early 
in  the  disease,  but  they  did  not  hesitate  to  give  it  even  late  in  the 
disease  if  the  cardiovascular  tone  was  good.  They  consider  the  state 
of  the  circulatory  apparatus  the  chief  factor  in  judging  whether  or 
not  the  patient  is  a  suitable  risk,  although  they  excluded  markedly 
cachectic  patients  as  well.  After  the  injection  improvement  in  the 
general  condition  of  the  patient  was  apparent  in  practically  every 
case. 

Slaymaker  reported  on  a  few  cases  treated  with  typhoid  vaccine 
given  intravenously,  the  dosage  varying  from  25  million  to  100  mil- 
lion. While  only  9  cases  were  treated  there  were  no  marked  re- 
sults, apart  from  some  evidence  of  reaction  and  improvement  in  two 
of  the  cases.  One  patient  died.  From  his  experience  Slaymaker  was 
not  inclined  to  continue  the  use  of  the  method.  Silvestri,  using  milk 
injections,  found  that  this  treatment  seemed  to  increase  the  tendency 
to  shock  and  hemorrhage  in  the  twelve  cases  that  he  observed. 

In  judging  the  relative  safety  or  danger  in  the  method  of  therapy 
it  may  be  well  to  present  briefly  the  statistics  recently  gathered  by 
Vaughan  in  the  American  Army  and  others  from  military  sources. 
These  represent  the  results  in  vaccinated  troops  and  may  be  considered 
quite  satisfactory  under  military  conditions. 


164 


PROTEIN  THERAPY 


Observer 

Cases 

Inocula- 
tions 

Mortality 
Per  Cent. 

26 

00 

4 

26 

2 

66 

Crossonini    

28 

3 

71 

50 

1-2 

80 

Campani  and  Gallotti  

86 

Hawn,  Hopkins  and  Meader  

38 

13.1 

15 

3-4 

133 

270 

11.0 

Total  A.  E.  F.,  11  months  

1242 

13.0 

5 

0.0 

Freund   

8.3 

If  we  compare  such  a  series  as  that  of  Holler  (350  cases)  with 
its  mortality  rate  of  about  %  of  1%,  to  the  statistics  collected  by 
Vaughan  it  would  seem  reasonable  to  conclude  that  the  nonspecific 
method  of  therapy  is,  with  reasonable  precautions,  rather  more  satis- 
factory than  the  mere  expectant  treatment. 

Kibler  and  McBride  noted  that  the  immediate  effects  of  the  intra- 
venous injection  of  the  typhoid  vaccine,  such  as  chill,  rise  and  fall 
of  temperature,  leukocytosis,  and  changes  in  the  concentration  of 
agglutinin  and  opsonin,  usually  in  the  direction  of  an  increase,  were 
the  same  in  the  normal  man  as  in  the  typhoid  patient.  Except  so 
far  as  they  showed  that  leukocytosis  is  rather  constant  after  the  in- 
jection of  vaccine,  they  did  not  support  any  particular  view  advanced 
to  explain  the  action  of  intravenous  injection  of  foreign  protein  in 
infectious  diseases.  The  number  of  cases  observed  (six) ,  possibly  too 
small  to  allow  any  conclusions  as  to  the  therapeutic  effect  of  typhoid 
vaccine  in  typhoid,  seemed  to  correspond  fairly  well  with  the  re- 
sults obtained  in  larger  series. 

Bacillus  carriers  have  been  treated  with  milk  injections  and  with 
intravenous  typhoid  (para)  vaccine  with  satisfactory  results.  Kar- 
rell  and  Luksch  have  employed  milk,  while  Herz,  using  vaccine  injec- 
tions, was  able  to  clear  up  4  out  of  5  patients. 

Discussion. — A  considerable  number  of  observers  have  endeavored 
to  determine  whether  or  not  there  is  an  increase  in  the  amount  of  anti- 
bodies in  the  serum  which  would 'account  for  the  recovery  of  the  patient 
after  nonspecific  therapy. 

The  general  summary  of  the  observations  on  this  particular  ques- 
tion is  that  while  such  an  increase  may  at  times  be  demonstrated,  it 
is  by  no  means  a  constant  result  of  the  injection  and  cannot  there- 
fore be  identified  as  being  the  sole  cause  of  the  abortive  recovery  of 


TYPHOID  AND  PARATYPHOID  FEVER  165 

the  patient.  The  agglutinin  titer,  which  has  been  most  often  studied, 
is  normally  found  to  be  rather  high  after  the  early  stage  of  typhoid 
fever  is  passed  and  after  nonspecific  injections  it  is  at  times  increased, 
at  other  times  diminished.  Nor  does  the  increase  or  decrease  bear  any 
relation  to  the  therapeutic  result.  Thus  Rohonyi  found  that  in  some 
of  his  patients  who  had  recovered  after  a  single  injection  by  a  critical 
drop  in  temperature,  there  was  no  increase  in  the  agglutinins,  in 
opsonins  or  in  bacteriolysin;  indeed  in  some  cases  he  was  able  to 
get  a  positive  blood  culture  two  days  after  the  patient  was  clinically 
free  from  every  evidence  of  active  disease — an  observation  which 
Decastello  has  not  been  able  to  confirm.  Llidke  was  not  able  to  de- 
termine any  constant  increase  in  the  amount  of  agglutinins  or  of 
opsinins  after  his  deutero-albumose  injections.  Baluit  observed  no 
change  in  the  agglutinins  or  the  bacteriocidal  antibodies,  but  obtained 
some  evidence  that  the  opsonins  were  increased.  Svestka  and  Marek 
found  no  increase  in  agglutinins.  Flechseder  on  the  other  hand  claims 
to  have  observed  an  increase  in  agglutinins  after  albumose  injections 
in  typhoid  fever. 

While  it  is  apparent  that  the  inconstant  results  exclude  the  anti- 
bodies as  sole  factors  in  the  recovery,  the  possibility  that  their  sud- 
den flooding  of  the  lymph  spaces  after  the  permeability  of  the 
capillaries  is  increased  following  the  protein  shock  may  be  a  vital 
factor  in  overcoming  the  infection. 

Whether  or  not  cell  receptors  (sessile  antibodies  that  may  have 
increased  in  amount  following  immunization  or  infection  without  their 
being  cast  off  into  the  general  circulation)  are  under  shock  conditions 
mobilized  and  in  this  way  increase  the  titer  after  nonspecific  therapy 
is  here  a  point  at  issue.  That  rabbits  immunized  to  some  specific 
bacterial  or  other  protein  may,  on  nonspecific  stimulation,  respond  by 
the  "shedding"  of  the  specific  antibody  is  an  old  observation.  Dieu- 
donne  observed  that  rabbits  immunized  with  typhoid  bacilli  and 
then  injected  with  "Hetol"  responded  by  an  increase  in  the  antibody 
production.  Solomonsen  and  Madsen  found  the  same  true  of  diph- 
theria horses  after  pilocarpin  injection,  and  Obermeier  and  Pick  found 
that  an  injection  of  5%  or  10%  peptone  increased  the  agglutinin 
titer  of  rabbits  immunized  more  than  3  months  previously.  Kutcher 
has  observed  that  patients  immunized  to  typhoid  and  cholera  will 
show  an  increase  in  the  agglutinins  for  dysentery  (paraspecific  ag- 
glutinins) and  the  mass  immunization  of  large  bodies  of  men  with 
typhoid  vaccine  gave  opportunity  during  the  course  of  the  war  to 
observe  that  many  varieties  of  shock  (acute  infectious  diseases  of 
various  kinds,  etc.)  were  followed  by  a  flooding  of  the  serum  of  such 
individuals  with  large  amounts  of  agglutinins.  Conradi  and  Bieling 
and  also  Johnson  made  experimental  observations  along  the  same 


166  PROTEIN  THERAPY 

line,  while  Parlovecchio  found,  as  had  Chantemesse,  that  the  injec- 
tion of  nucleins  increased  the  agglutinin  and  alexin  titer.  Ardin- 
Delteil,  Negre  and  Raynaud  have  also  reported  increase  of  agglutinins 
and  bactericidal  substances  in  serum  after  nonspecific  injections. 
Other  procedures  include  the  stimulation  of  the  sympathetics  (Stuber), 
the  injection  of  alcohol  (Friedberger) ,  arsenic  (Agazzi),  salvarsan 
(Friedberger  and  Masuda),  blood-letting  (Friedberger  and  Dorner), 
all  of  which  are  followed  by  an  increase  in  antibody  titer. 

It  seems  very  probable  that  when  the  cells  have  become  im- 
munized during  the  course  of  the  disease,  a  certain  number  of  re- 
ceptors are  available  but  have  not  been  shed.  These  are  possibly 
mobilized  when  nonspecific  injections  are  made. 

In  a  previous  chapter  the  possible  mechanism  that  underlies  the  re- 
covery in  typhoid  fever  by  means  of  nonspecific  therapy  has  been 
fully  discussed,  so  that  it  will  not  be  necessary  to  again  enter  into 
the  subject  here. 

A  number  of  interesting  questions  present  themselves,  however, 
as  a  result  of  clinical  observation  in  more  recent  years  concerning 
the  normal  recovery  from  typhoid  fever.  In  persons  who  have  been 
previously  sensitized  or  immunized  the  course  of  the  disease  is  fre- 
quently more  stormy  and  somewhat  shortened  while  the  difference 
in  the  mortality  may  not  be  great  as  contrasted  with  the  unvaccinated. 
On  the  other  hand  we  know  that  recovery  can  take  place  without 
the  appearance  of  antibodies  in  the  blood  stream,  as  Moreschi  has 
demonstrated  in  leukemia.  Certainly  the  presence  or  absence  of  the 
antibodies  can  no  longer  be  made  responsible  for  the  clinical  course 
of  the  disease. 

On  the  other  hand  the  period  of  defervescence  with  its  great  varia- 
tions in  the  daily  temperature  curve  is  very  suggestive  of  the  reaction 
of  the  organism  to  nonspecific  injections.  One  can  conceive  that  the 
daily  accumulation  of  toxic  proteins  produces  a  summation  of  toxic 
effects  with  a  resulting  effect  on  the  temperature  curve.  After  the 
"shock"  effect  has  passed  the  remission  with  its  alteration  in  perme- 
ability and  cellular  stimulation,  sets  in  and  as  the  process  is  kept 
up  the  organism  gradually  becomes  resistant  to  the  intoxication  un- 
til finally  defervescence  is  complete.  The  study  of  Aller  would  rather 
confirm  this  conception;  he  presents  a  number  of  interesting  examples 
which  cannot  be  discussed  in  detail  at  this  place.  Holler's  work 
would  lead  one  to  suspect  such  a  basis  for  the  normal  mechanism 
of  recovery  for  when  he  injected  his  proteoses  in  daily  small  doses 
similar  temperature  effects  were  achieved  and  the  patient  was  soon 
completely  afebrile.  Liidke  has  recently  expressed  this  same  view. 

So,  too,  one  can  observe  a  variety  of  modifications  of  the  tempera- 
ture curve  even  after  a  single  nonspecific  injection.  The  crisis  may 
be  prompt  and  complete.  In  other  cases  where  a  continuous  high 


TYPHOID  AND  PARATYPHOID  FEVER      167 

temperature  has  been  observed,  daily  remissions  in  the  temperature 
curve  will  set  in  after  a  single  injection;  in  others  the  average  height 
of  the  temperature  curve  may  be  altered  so  that  from  a  continuous 
temperature  of  about  102°  F.  the  temperature  after  the  injection 
will  have  a  level  around  100°  F.,  as  though  the  heat  regulation  had 
been  attuned  to  a  new  level. 

The  question  of  the  mechanism  of  recovery  brings  with  it  the 
query,  When  is  the  patient  cured?  Does  freedom  from  symptoms  con- 
stitute cure?  It  has  been  pointed  out  that  after  the  therapeutic  crisis 
a  positive  blood  culture  may  still  be  obtained,  the  spleen  may  still 
be  palpable  for  a  few  days,  the  roseola  remains  a  short  time,  the  diazo 
reaction  may  persist,  etc.,  the  while  the  patient  will  be  free  from 
fever  and  in  excellent  condition.  As  a  result  of  the  treatment  the 
body  does  not  react  to  the  typhoid  bacteria.  It  is  desensitized,  not 
necessarily  free  from  the  infection.  Very  likely,  though,  a  similar 
condition  obtains  frequently  during  normal  recovery  from  typhoid 
fever  as  is  evidenced  by  the  persistence  of  bacteria  in  the  bile  tracts, 
the  gastro-intestinal  and  urinary  systems  or  in  the  isolated  foci  that 
may  become  manifest  weeks  after  the  clinical  recovery  from  the  febrile 
course.  As  a  matter  of  fact  Holler  found  no  cases  of  carriers  in  his 
350  cases  of  typhoid  fever  treated  with  proteoses,  and  Herz  states 
that  typhoid  carriers  can  be  freed  following  protein  therapy.  Re- 
lapses occur  occasionally,  but  Liidke  observed  that  these  were  much 
milder  in  character  and  of  shorter  duration  than  in  untreated  cases. 
Bresler  in  his  review  of  modern  typhoid  treatment  brings  out  the 
fact  that  the  small  number  of  relapses  in  cases  treated  with  non- 
specific injections  is  quite  apparent  and  he  also  believes  that  a  dis- 
tinct improvement  of  the  circulation  takes  place  even  when  there  has 
been  no  direct  effect  on  the  temperature. 

The  observation  of  Wiesner  to  the  effect  that  the  typhoid  ulcers 
•commence  healing  immediately  after  the  therapeutic  injection  is  of 
interest  in  this  connection.  From  the  therapeutic  standpoint  it  is 
naturally  important  that  the  patient,  even  after  defervescence,  should 
oe  kept  quiet  in  bed  for*  at  least  ten  days  and  longer  if  there  is  any 
evidence  of  myocardial  impairment. 

•  Therapeutic  Precautions. — There  are  three  chief  dangers  that  must 
De  kept  in  mind  in  the  treatment  of  typhoid  fever  by  nonspecific 
therapy.  The  first  concerns  intoxication.  When  we  are  dealing  with  a 
profoundly  toxic  patient  we  must  be  reasonably  certain  that  he  is  able 
to  bear  the  increase  in  intoxication  which  seemingly  occurs  after  the 
nonspecific  injection  and  which  is  probably  due  to  a  rapid  destruction 
of  typhoid  bacteria.  We  have  observed  one  such  case  in  a  profoundly 
intoxicated,  obese  typhoid  patient  who,  despite  the  gravity  of  the  risk 
involved,  was  injected  with  a  small  dose  of  proteoses  and  died  within 


168  PROTEIN  THERAPY 

an  hour  following  the  chill.  At  autopsy  no  lesions  other  than  those 
of  typhoid  fever  and  a  marked  cloudy  swelling  of  all  parenchymatous 
tissues  and  a  toxic  myocarditis  were  observed. 

The  other  two  dangers  are  related  to  the  gastro-intestinal  tract. 
When  nonspecific  therapy  is  used  the  intestinal  tract  is  affected  to 
a  considerable  degree,  depending  on  the  severity  of  the  reaction,  the 
agent  used,  etc.  There  is  first  of  all  an  increased  motility.  Coinci- 
dent with  it  there  is  an  engorgement  of  the  vessels  of  the  bowel.  Both 
of  these  factors  may  result  in  an  increased  possibility  of  perfora- 
tion and  of  hemorrhage. 

Clinicians  who  have  had  largest  experience  with  the  treatment  of 
typhoid  fever  state  very  definitely  that  these  dangers  are  theoretical 
rather  than  actual.  When  fatalities  occur  following  the  treatment  the 
dosage  employed  in  producing  the  reaction  may  have  been  too  large  or 
the  agent  selected  not  the  best  one  for  use.  The  injection  of  both 
typhoid  bacilli  and  also  of  proteoses  is  not  followed  by  the  styptic  effect 
that  we  see  after  milk  injections,  and  the  vaccine,  too,  has  the  added 
disadvantage  of  being  decidedly  toxic  in  itself,  both  factors  that  would 
incline  one  to  favor  any  of  the  other  agents  rather  than  the  typhoid 
vaccine.  The  question  of  dosage  is  one  that  has  not  been  definitely 
settled.  Of  course,  the  massive  doses  of  typhoid  bacilli  that  have  at 
times  been  employed  (1  billion  and  more)  by  American  observers 
and  which  were  naturally  followed  by  disasters  of  various  kinds 
should  not  be  countenanced  in  typhoid  fever,  however  well  they  may 
be  tolerated  in  other  conditions. 

When  typhoid  vaccine  is  used  only  enough  organisms  should  be 
injected  to  provoke  a  mild  reaction — from  10  to  25  million — and  sim- 
ilarly moderate  doses  with  other  bacterial  vaccines.  When  relatively 
nontoxic  agents  are  employed  such  as  proteoses,  colloidal  metals, 
nucleins,  etc.,  one  can  follow  two  courses.  Either  to  give  sufficient 
to  provoke  a  general  reaction  and  perhaps  repeat  the  dose  after  sev- 
eral days  if  the  fever  has  not  been  altered,  or  give  small  daily  doses, 
none  of  which  are  themselves  sufficient  to  provoke  a  severe  reaction. 
Holler  has  used  this  latter  method  with  success ;  it  is  the  method  that 
Jobling  and  the  writer  have  preferred  to  follow  when  dealing  with 
typhoid  fever.  The  immediate  results  may  not  be  quite  as  brilliant  as 
when  larger  doses  are  used,  but  there  is  certainly  much  less  danger 
of  precipitating  some  decidedly  grave  complication.  For  general 
use  we  cannot  too  urgently  emphasize  these  considerations. 

In  order  to  overcome  some  of  these  potential  dangers,  Neustadl 
and  Marcovici  usually  prepared  their  patients,  especially  those  that 
had  been  ill  for  some  time  and  in  whom  there  were  evidences  of  vaso- 
motor  instability,  with  digitalis.  Jobling  and  the  writer  tried  to 
overcome  the  motor  activity  of  the  gastro-intestinal  tract  and  the 


TYPHOID  AND  PARATYPHOID  FEVER  169 

consequent  danger  of  hemorrhage  and  perforation  by  using  opiates  be- 
forehand. There  seemed  to  be  little  control,  however,  of  the  in- 
crease in  peristalsis.  Zupink,  Miiller  and  Leiner,  Matko  and  Holler 
stimulated  their  cases  with  caffein  given  before  the  injections. 

If  the  pulse  is  over  100  and  there  are  evidences  of  vasomotor 
instability,  if  the  patient  is  profoundly  toxic  or  cachectic,  if  there 
has  been  any  bleeding — epistaxis,  gastro-intestinal,  etc.,  if  cyanosis 
is  present,  if  the  disease  has  continued  for  several  weeks  before  treat- 
ment is  commenced,  or  if  there  is  any  evidence  of  pneumonic  compli- 
cations, it  is  not  advisable  to  try  nonspecific  therapy.  If  given  under 
such  conditions  the  clinician  must  consider  the  dangers  involved 
and  seriously  weigh  the  chances  for  collapse  or  hemorrhage  or  per- 
foration and  determine  whether  or  not  they  are  overbalanced  by 
possible  advantages, 

PARATYPHOID  FEVER 

It  will  be  recalled  that  Ichikawa  treated  a  number  of  paratyphoid 
cases  with  typhoid  vaccine  with  good  results. 

Holler  in  his  series  of  infectious  diseases  treated  140  cases  of 
paratyphoid  fever  with  small  daily  injections  of  deutero-albumoses. 
There  were  7  deaths  in  this  series. 

The  indications  and  contra-indications  are  those  that  have  been 
discussed  under  the  subject  of  typhoid  fever. 


CHAPTER  X 
GONORRHEA  AND  ITS  COMPLICATIONS 

The  intravenous  injection  of  vaccines  in  the  treatment  of  gonor- 
rheal  complications  is  a  procedure  that  antedates  by  a  few  years  the 
more  general  application  that  we  now  consider  under  the  subject  of 
protein  therapy.  Bruck  and  Sommer  had  in  1912  and  1913  made  use 
of  a  polyvalent  gonococcus  vaccine  for  intravenous  injections  in  a 
variety  of  complications,  such  as  arthritis,  epididymitis  and  acute 
prostatitis,  with  remarkable  results.  Within  certain  limits  their  re- 
sults paralleled  the  severity  of  the  systemic  response  that  followed 
on  the  vaccine  injection.  The  reaction  that  was  observed  consisted 
of  the  usual  rise  in  temperature,  a  leukocytosis,  occasional  chill  and 
sweating,  etc.  It  will  be  recalled  that  previously  the  morphological 
similarity  of  the  gonococcus  and  the  meningococcus  had  led  Herescu 
and  Strominger  to  use  antimeningococcus  serum  therapeutically 
against  gonococcus  infections. 

That  fever  or  at  any  rate  intercurrent  infections  have  at  times 
a  decided  effect  in  altering  the  course  of  a  venereal  infection  and  its 
complications  had  been  noted  for  a  number  of  years  and  had  been  dis- 
cussed by  Finger,  Gohn  and  Schlagenhaufer  in  1895.  In  1916  Miiller 
and  Weiss  reported  excellent  results  in  gonorrheal  complications  with 
their  intergluteal  injections  of  milk  and  a  nucleinate,  similar  to  those 
of  Bruck  and  Sommer.  A  number  of  workers  at  once  made  prelimi- 
nary trials  of  the  method  in  this  clinical  field,  including  Schmidt,  v. 
Tanner,  Friedlander,  Elschnig,  Luithlen,  etc. 

Smith  in  this  country  had  independently  come  to  a  similar  point 
of  view  in  the  treatment  of  patients  suffering  from  gonorrheal  compli- 
cations in  using  specific  sera  or  normal  horse  serum.  Some  of  these 
became  more  or  less  sensitized  to  the  serum  and  on  further  in- 
jection, responded  with  a  decided  general  reaction.  These  patients 
in  particular  were  the  ones  that  gave  the  most  promising  clinical 
results,  so  that  Smith  emphasized  the  importance  of  this  state  of  sensi- 
tization  and  the  coincident  temperature  rise  in  the  therapeutic  result 
obtained.  The  experimental  research  reported  by  Arloing,  Dufourt  and 
Langeron  confirms  the  clinical  observation  that  it  may  be  possible 
to  cure  certain  infections  by  inducing  an  anaphylactic  shock.  The 
research  was  done  on  guinea-pigs  inoculated  with  pyocyaneus 
cultures.  Even  a  slight  shock  was  enough  to  arrest  the  infectious 
process.  The  clinical  cure  was  accompanied  by  the  destruction  of 
the  germs  in  the  blood  and  by  the  acquirement  of  immunity. 

170 


GONORRHEA  AND  ITS  COMPLICATIONS  171 

Culver's  Investigation  of  Gonorrheal  Arthritis. — These  reports 
led  Culver  to  investigate  the  specificity  of  the  therapeutic  procedure. 
He  selected  a  series  of  cases  suffering  from  gonorrhea  and  some  com- 
plications (arthritis,  etc.) ;  these  were  divided  into  four  groups,  the 
first  of  which  was  treated  by  the  intravenous  injection  of  a  gonococ- 
cus  vaccine,  the  second  a  similar  dose  of  meningococci,  the  third  of 
colon  bacilli,  the  fourth  of  a  deutero-albumose  solution.  No  local 
or  general  treatment  other  than  the  injections  was  given. 

Gonococcus  Vaccine. — In  the  first  series  Culver  gave  100  million 
killed  gonococci  and  repeated  the  dose  every  fourth  or  fifth  day.  The 
greatest  number  of  injections  given  one  person  was  6,  most  of  them 
received  5,  one  received  but  one  injection.  The  injections  were  fol- 
lowed by  a  chill  of  variable  severity  coming  on  in  20  minutes  to  1 
hour  and  lasting  15-30  minutes.  The  chill  was  at  times  accompanied 
by  headache,  usually  of  short  duration.  Exceptionally,  there  was 
nausea  and  vomiting  during  the  first  few  hours,  but  never  severe  and 
always  transient.  This  occurred  often  in  patients  who  had  disobeyed 
instructions  by  eating  heartily  within  a  few  hours  of  the  injection. 

At  the  onset  and  during  the  chill  the  patient  often  complained  of 
severe  pain  in  the  affected  parts  (focal  reaction). 

Invariably  the  disagreeable  effects  of  the  reactions,  if  any  appeared, 
disappeared  in  about  24  hours,  and  for  the  next  24-72  hours  a  variable 
degree  of  comfort  was  experienced.  The  pain  and  the  tenderness, 
together  with  the  swelling  of  the  joints,  were  much  improved.  This 
prompt  improvement  was  most  likely  to  be  of  only  2-4  days'  duration, 
and  then  there  was  a  stiffness  of  the  affected  joints  with  some  pain 
on  motion,  but  usually  in  a  much  less  severe  form. 

These  relapses  gradually  decreased  in  severity  following  succes- 
sive injections  until  eventually  none  appeared.  In  some  instances 
there  was  no  relapse,  even  following  the  first  injection. 

Injections  were  repeated  on  the  3rd-5th  day,  or  usually  just  as  the 
joints  began  to  show  a  return  to  their  old  condition.  This  seems  to 
be  a  more  efficient  method  of  injecting  than  daily  injections.  With 
daily  injections,  the  patient  is  at  all  times  having  a  reaction  or  just 
recovering  from  one.  His  general  condition  is  not  so  good  nor  does  the 
local  disease  respond  so  well. 

It  is  usual  for  the  severity  of  the  reaction  to  decrease  following 
repeated  injections,  and  this  decrease  seemed  directly  proportional 
to  the  number  of  injections  previously  given. 

In  patients,  both  of  whom  had  numerous  subcutaneous  injections 
of  gonococcal  vaccine,  there  appeared  immediately  following  each  in- 
travenous injection  a  very  transient  reaction  characterized  by  flush- 
ing of  the  face,  cyanosis,  dyspnea,  and  a  tingling  sensation  over  the 
surface  of  the  whole  body.  These  reactions  lasted  1-2  minutes,  after 
which  the  patients  felt  perfectly  at  ease  until  the  usual  reaction  ap- 


172  PROTEIN  THERAPY 

peared  in  20  minutes-1  hour.  This  anaphylactic-like  reaction  may  have 
been  due  to  a  partial  sensitization  from  the  previous  subcutaneous 
injections.  Three  other  patients  in  this  series  developed  a  mild  type 
of  a  very  similar  condition,  on  the  3rd  intravenous  injection. 

The  typical  temperature  curve  following  these  injections  revealed 
a  slight  fall  during  the  first  part  of  the  chill,  followed  by  a  gradual 
rise,  which  reached  its  maximum  in  4-6  hours,  and  gradually  fell  to 
normal  in  24  hours. 

The  leukocyte  counts  during  a  reaction  and  following  were  some- 
what variable.  Usually  a  mild  leukocytosis  just  before  and  during 
the  first  part  of  the  chill  was  observed,  soon  followed  by  a  marked 
leukopenia,  which  appeared  toward  the  end  of  the  chill;  a  count  as 
low  as  2,000  being  observed  repeatedly  during  this  stage  of  the  re- 
action. This  condition  was  soon  followed  by  a  gradually  developing 
leukocytosis,  reaching  its  maximum  in  5-7  hours,  and  remaining  mod- 
erately high  for  24-30  hours.  A  return  to  normal  occurred  in  about 
48  hours. 

Meningococcus  Vaccine. — The  second  series  of  15  patients  was 
treated  with  killed  meningococci  in  the  same  dose  and  at  similar 
intervals  as  in  the  gonococcus  series. 

The  reactions  as  far  as  could  be  determined  were  similar  in  every 
detail  to  those  produced  by  the  gonococcus  vaccine.  One  instance  of 
at  double  reaction  occurred  following  the  1st  injection,  and  1  patient 
developed  this  condition  after  2  injections.  None  of  this  series  had 
had  previous  subcutaneous  or  intravenous  injections. 

The  leukocyte  curve,  in  general,  likewise  followed  that  of  the  first 
series  very  closely.  One  very  startling  difference  was  observed  be- 
tween the  2  groups.  Over  one-half  the  meningococcus  series  de- 
veloped a  more  or  less  severe  herpes  of  the  lips  and  mucous  membrane 
of  the  mouth,  first  appearing  in  48  hours  and  remaining  for  4-7  days. 
This  condition  did  not  follow  any  but  the  1st  injection,  and  did  not  be- 
come aggravated  or  recur  when  further  injections  were  made  in 
a  susceptible  person. 

Colon  Bacillus  Vaccine. — This  series  contained  but  9  patients. 
The  reactions  were  in  every  way  like  those  produced  by  meningococcus 
and  gonococcus  with  the  exception  that  the  size  of  the  dose  required 
to  produce  the  same  results  was  very  much  less.  At  first  a  dose  of 
100  million  organisms  was  given,  but  the  reactions  were  so  severe  that 
25  million  were  finally  used  as  the  initial  dose,  this  to  be  increased 
if  necessary  to  produce  the  desired  results. 

Deutero-albumose. — A  secondary  proteose  made  from  casein  was 
used  (80  mg.)  in  4%  solution  on  a  series  of  4  patients,  the  initial 
dose  being  2  c.c.  The  reaction  showed  some  variations  from  those 
produced  by  bacterial  suspensions,  in  that  the  chill  never  took  place 
before  1  hour  after  the  injection,  and  that  there  was  no  headache  or 


GONORRHEA  AND  ITS  COMPLICATIONS  173 

nausea  following  any  of  the  injections;  also  the  fever  and  leukocytosis 
did  not  reach  the  height  produced  by  bacterial  suspensions.  Sufficient 
experience  with  this  solution,  however,  was  gained  to  convince 
one  that  the  reaction  and  therapeutic  effects  are  very  similar  and 
equally  as  effective  as  those  produced  by  bacterial  suspensions,  as 
well  as  giving  rise  to  less  disagreeable  reactions. 

As  far  as  therapeutic  results  are  concerned  there  was  no  notice- 
able difference  between  the  3  bacterial  suspensions  or  the  albumose 
solution.  To  produce  results  therapeutically  a  reaction  is  necessary. 
That  is,  a  chill  must  occur  which  is  invariably  followed  by  the 
temperature  and  leukocyte  changes  noted.  A  dose  insufficient  to  pro- 
duce a  definite  chill  was  not  followed  by  as  marked  a  temperature 
as  the  leukocytic  reaction,  and  clinically  there  was  not  only  no  thera- 
peutic benefit,  but  sometimes  patients  became  more  uncom- 
fortable than  before.  The  reactions  following  injections  in  non- 
gonorrheal  patients  were  not  to  be  distinguished  from  those  produced 
in  infected  patients. 

These  observations  were  made  by  injecting  a  series  of  patients 
with  chronic  skin  lesions  with  no  history  or  indication  of  gonococcal 
infections.  The  size  of  the  dose  required  to  produce  a  reaction,  the 
chill,  temperature,  and  leukocytosis  was  alike  in  every  way  in  the 
infected  and  the  noninfected  patients. 

Thirty-one  patients  suffering  from  arthritis  associated  with  gonor- 
rheal  urethritis  were  treated.  Most  of  these  cases  were  acute  or  sub- 
acute,  but  some  were  of  5  months'  duration,  and  many  were  over 
10  weeks'  duration  when  the  treatment  was  begun. 

As  might  be  expected,  the  most  striking  results  were  obtained  in 
the  acute  and  subacute  cases;  however,  the  most  refractory  instances 
were  also  in  the  acute  class.  Those  suffering  for  long  periods  appeared 
to  respond  more  slowly  to  the  treatment,  but  fortunately  seemed  to 
suffer  from  no  recurrence  or  new  joint  involvements  during  the  course 
of  the  treatment.  All  but  3  of  the  arthritic  patients  were  apparently 
completely  cured  or  manifested  a  decided  improvement.  The  length 
of  treatment  varied  from  2  days  to  1  month. 

Unusual  effects  were  seen  in  3  patients  with  acute  arthritis,  so 
severe  that  sedatives  were  necessary  to  give  them  rest  for  the  first  2 
days  in  the  hospital.  After  a  single  reacting  dose  in  each  instance 
they  felt  so- well  that  they  insisted  on  getting  out  of  bed,  and  in  3 
days  they  walked  from  the  hospital.  Two  of  the  patients  had  effu- 
sions in  the  knee  joints,  which  completely  disappeared  before  their 
discharge  from  the  hospital.  Equally  striking  was  the  instance  of  a 
man  who  had  been  confined  to  his  bed  for  4  weeks  with  arthritis  of 
almost  every  joint  of  both  lower  extremities.  These  lesions  had  come 
on  during  the  third  week  of  gonorrhea.  After  the  third  injection,  he  was 


174  PROTEIN  THERAPY 

up  and  walking  about,  and  after  the  6th  injection  he  was  apparently 
completely  cured. 

The  3  refractory  cases  mentioned  were  all  acute,  and  seemed  not 
to  respond  at  all  or  very  slowly  to  this  form  of  treatment.  One  would 
show  considerable  improvement  for  a  day  or  two,  but  invariably  would 
lapse  back  to  the  original  condition ;  a  second  recovered  completely  ex- 
cepting one  knee  joint,  which  contained  a  marked  effusion  and  seemed 
not  to  be  affected  by  repeated  injections,  while  the  third  did  not  re- 
spond from  the  first  to  repeated  injections  of  albumose  solution. 

Bruck  noticed  similar  refractory  cases  which  he  explained  by  the 
absence  of  the  homologous  gonococcus  strain  from  his  polyvant  vac- 
cine. It  is  evident  that  this  explanation  will  not  suffice,  but  whether 
it  is  due  to  a  special  resisting  power  of  the  particular  infecting  gono- 
coccus or  to  some  peculiarity  of  the  infected  host,  it  is  impossible  to 
say.  Such  patients  react  with  fever  and  leukocytosis  as  do  all  others. 

Epididymitis. —  Twelve  patients  with  acute  epididymitis  were 
treated,  and  invariably  the  pain  would  subside  after  the  first  injection. 
Usually  not  more  than  two  injections  were  necessary,  and  indeed  in 
most  instances  one  proved  sufficient  to  effect  a  cure.  The  swelling 
began  to  subside  within  24  hours  after  the  first  injection.  In  no  instance 
did  the  patient  remain  in  the  hospital  over  a  week,  excepting  in  one 
case  in  which  an  overdose  was  given. 

That  these  injections  are  not  prophylactic  against  the  development 
of  new  complications  is  evidenced  by  the  fact  that  occasionally  one 
sees  a  patient  under  treatment  develop  an  acute  epididymitis  or  an 
involvement  of  a  new  joint.  Again,  a  patient  may  leave  apparently 
cured  of  arthritis  to  return  in  a  few  weeks  suffering  from  epididymitis. 

On  account  of  the  fact  that  the  reaction  following  these  injections 
is  followed  by  a  chill  and  general  reaction  of  more  or  less  severity, 
a  very  complete  physical  examination  is  necessary  beforehand.  Such 
a  reaction  necessarily  calls  for  increased  cardiac  activity,  so  one  should 
proceed  with  caution  when  a  patient  with  coexisting  organic  heart 
disease  presents  himself.  The  smallest  reacting  dose  of  meningococci 
was  given  to  one  man  who  was  suffering  from  mitral  regurgitation  of 
long  standing  but  perfectly  compensated,  together  with  acute  epi- 
didymitis. He  passed  through  the  chill  with  no  distress,  but  in  three 
hours  after  the  injection  he  became  cyanotic,  his  pulse  became  irregu- 
lar and  feeble,  and  he  had  marked  precordial  pain.  This  condition 
lasted  10-15  minutes,  and  he  had  no  further  inconvenience.  No 
other  cardiac  irregularities  were  noted  in  the  entire  series.  Arnold 
and  Holzel  cite  Lewinskies  case  of  acute  cardiac  insufficiency  develop- 
ing after  the  intravenous  injection  of  gonococci.  Heart  disease  was 
not  known  to  be  present.  On  the  other  hand,  Luithlen  reports  a  case  of 
gonorrheal  endocarditis  successfully  treated  in  this  manner.  There 
are  many  instances  reported,  however,  of  cardiac  symptoms  develop- 
ing in  the  presence  of  organic  heart  disease  following  these  injections, 


GONORRHEA  AND  ITS  COMPLICATIONS  175 

so  one  should  exercise  care  and  judgment  in  the  selection  of  cases. 

Renal  Involvement. — From  the  proper  dosage  in  this  series,  there 
were  noted  no  other  symptoms  attributable  to  the  injections.  Special  at- 
tention was  given  the  kidney  function,  particularly  in  three  patients 
who  had  received  large  doses  of  colon  bacilli.  In  no  instance  did  al- 
bumin appear  in  the  urine,  nor  did  any  indication  of  kidney  involve- 
ment arise.  One  patient  having  a  chronic  diffuse  nephritis  with  con- 
siderable albumin  in  the  urine  had  two  injections  with  no  appreciable 
change  in  the  kidney  function. 

This  seems  to  be  significant,  as  Breed  and  others  had  found  that 
there  is  quite  a  marked  increase  in  nitrogen  output  after  such  a  re- 
action, this  increase  being  maximum  on  the  sixth  day.  She  advises  a 
low  protein  diet  for  a  few  days  before  such  injections  to  prevent  a 
possible  kidney  change. 

Foekler  reported  epileptiform  seizures  after  similar  intravenous  in- 
jections, and  Fischer  in  one  instance  noted  cerebral  symptoms,  which 
passed  off  in  24  hours. 

Delirium  was  noted  in  three  patients  of  this  series,  all  of  which  had 
received  large  doses  of  colon  bacilli. 

Culver  was  particularly  impressed  with  the  possibility  that  the 
febrile  reaction  itself,  the  mere  increase  in  the  body  temperature  might 
be  involved  in  the  therapeutic  effectiveness  of  the  nonspecific  therapy. 
A  number  of  observers  who  at  former  times  considered  this  factor  in 
resistance  to  infection  and  recovery  from  disease,  among  them  Wal- 
ther,  Hildebrand,  Englehardt,  Roily  and  Meltzer,  have  reached  the 
conclusion  that  high  temperature  artificially  produced  has  a  favorable 
influence  on  any  established  infection;  on  the  other  hand,  cold  seems 
to  retard  the  formation  of  immune  bodies.  The  optimum  temperature 
for  the  growth  of  the  gonococcus  in  vitro  is  97° -98°  F.  Any  appreci- 
able increase  in  temperature  has  a  very  deleterious  effect  on  the  life 
and  growth  of  the  organism.  A  sudden  rise  to  102°  F.,  or  over,  means 
certain  death  of  the  culture. 

When  acute  epididymitis  develops,  does  the  fever  produced  thereby 
have  anything  to  do  with  the  spontaneous  cure  of  gonorrhea?  Many 
patients  with  infections  terminating  thus  have  had  considerable  fever 
during  the  onset  of  the  complication.  On  the  other  hand,  patients  are 
seen  with  infections  terminating  in  a  similar  manner  having  had  a 
normal  temperature  throughout;  this,  however,  does  not  seem  to  be 
a  common  occurrence. 

Experimental  urethritis  in  man  has  been  produced,  but  Finger, 
Gohn,  and  Schlagenhaufer  regularly  failed  when  the  experimental 
patient  had  a  temperature  of  102.2°-104°  F.  due  to  some  preexisting 
disease. 

Culver  calls  attention  to  a  patient  who  entered  the  hospital  with 
acute  urethritis  of  3  days'  duration.  A  positive  gonococcus  culture 
was  obtained  on  entrance.  The  second  day  in  the  hospital  he  had  a 


176  PROTEIN  THERAPY 

chill,  followed  by  a  temperature  of  105°  F.  Malarial  parasites  were 
found  in  the  blood,  but  the  chills  and  fever  were  allowed  to  con- 
tinue for  4  days,  at  the  end  of  which  time  all  evidence  of  local  in- 
fection had  disappeared.  He  remained  in  the  hospital  for  2  weeks, 
without  recurrence  of  the  infection,  having  had  no  local  treatment 
whatever.  The  influence  of  fever  on  these  infections  in  the  medical 
wards  is  of  course  well  known;  one  rarely,  if  ever,  sees  a  gonorrheal 
infection  coexisting  with  some  fever-producing  disease  like  pneu- 
monia, typhoid,  or  malaria  while  gonorrheal  infections  are  relatively 
common  among  the  chronic  nonfebrile  conditions. 

The  therapeutic  results  in  the  group  which  forms  the  basis  of  this 
report  very  noticeably  correspond  to  the  temperature  increase  and 
to  hyperleukocytosis.  Considering  the  fact  that  the  gonococcus  is 
heat  sensitive  both  in  vitro  and  in  vivo;  that  fever  patients  cannot 
be  experimentally  infected  with  the  gonococcus;  that  a  fever-produc- 
ing disease  spontaneously  cures  previously  existing  gonorrheal  in- 
fections, there  can  be  but  little  question  that  fever  artificially  pro- 
duced plays  some  part  in  the  recovery  from  these  infections. 

How  much  influence,  if  any,  the  leukocyte  increase  in  the  peripheral 
circulation  has,  cannot  easily  be  determined,  for  when  artificially 
produced  in  the  manner  employed  here,  the  fever  and  hyperleukocytosis 
are  invariably  present  together. 

It  is  apparent  that  the  usual  treatment  of  gonorrheal  arthritis  is 
not  satisfactory  in  all  instances,  when  almost  daily  one  can  see  an 
ankylosed  joint  and  atrophied  muscles  following  this  condition.  Should 
this  treatment  by  intravenous  protein  injections  prove  to  give  perma- 
nent results  in  this  condition,  as  present  data  seem  to  indicate,  are 
we  justified  in  using  such  a  measure?  In  view  of  the  chronicity  of  the 
disease  and  the  destructive  complications  that  commonly  arise  it 
would  appear  to  be  a  rational  procedure  when  properly  used  and 
controlled.  However,  until  some  substance  is  obtained  whose  dosage 
can  be  more  definitely  standardized,  it  would  seem  that  this  form  of 
treatment  should  not  be  generally  used  by  those  not  thoroughly  fa- 
miliar with  the  reaction  and  the  manner  of  regulating  the  size  and 
interval  of  dosage  of  such,  as  used  in  the  work  here  reported. 

In  a  recent  review  of  his  work  Culver  states  that  in  his  experi- 
ence at  one  of  the  military  camps  during  the  war  where  intravenous 
injections  of  gonococcus  protein  was  made  in  every  case  of  epi- 
didymitis,  the  results  were  most  satisfactory,  the  average  stay  in  the 
hospital  being  from  5  to  6  days.  Even  the  primary  localization  of 
the  organism  in  the  urethra  or  extensions  of  the  infection  into  the 
prostate  and  seminal  vesicle  responded  more  readily  to  local  treatment 
after  nonspecific  injections  of  this  kind  than  cases  not  injected. 

Since  the  publication  of  these  papers  by  Culver  a  considerable 
literature  on  the  subject  has  been  accumulating,  all  of  which  reveals 
practically  the  same  general  clinical  experience — namely,  that  non- 


GONORRHEA  AND  ITS  COMPLICATIONS  177 

specific  therapy  is  of  decided  usefulness  in  the  treatment  of  gonor- 
rheal complications,  either  local  or  remote,  but  that  in  the  treat- 
ment of  the  primary  infection  of  the  mucous  membrane  itself  our  older 
methods  are  of  greater  value  and  dependability,  although  certain 
observers  are  of  the  opinion  that  as  an  adjunct  method  of  treatment 
it  has  its  decided  value  even  here. 

Keyes  makes  the  following  statement:  "It  is  not  generally  ap- 
preciated that  the  reason  for  the  extreme  susceptibility  to  recurrence 
of  joint  lesions  with  each  gonorrhea,  in  a  patient  who  has  once  had 
arthritis,  is  a  susceptibility  in  the  joint,  not  in  the  urethra.  At  its 
onset  the  use  of  vaccines  or  serum  may  be  worth  while.  Two  or 
three  doses  of  antigonococcus  serum  at  the  moment  when  a  joint  is 
beginning  to  become  inflamed  may  abort  the  infection,  as  may  also 
a  heavy  dose  of  gonococcus  vaccine;  this  usually  by  the  systemic  re- 
action produced. 

"But  once  the  joint  infection  is  established,  vaccines  are  not  to 
be  relied  on.  I  have  tried  all  the  specific  and  nonspecific  forms  that 
have  been  commended  to  me,  including  horse  serum  and  typhoid  vac- 
cines administered  intravenously.  If  these  are  employed  in  suffi- 
cient dose  to  give  a  systemic  reaction,  a  temporary  benefit  may  be 
obtained,  and  occasionally  a  permanent  benefit.  But  the  rule  is  that 
these  treatments  do  not  appreciably  influence  the  course  of  the  dis- 
ease." 

Luithlen  has  had  considerable  experience  in  the  treatment  of  gonor- 
rheal  complications,  using  an  intravenous  injection  of  gonococci  (100 
million  to  the  c.c.)  as  a  rule  to  elicit  the  reaction;  he  specifically 
recommends,  though,  that  local  treatment  should  in  no  instance  be 
neglected.  In  the  treatment  of  old  torpid  venereal  ulcers,  soft  chancres 
and  ulcers  persisting  after  buboes  he  injects  about  50  million 
organisms  intravenously  two  or  three  times  at  intervals  of  several 
days,  or  if  intramuscular  injection  is  preferred  injects  from  300  to 
500  million,  in  some  cases  as  much  as  800  million  organisms. 

Bloch,  who  recognized  that  the  vaccine  therapy  as  used  in  in- 
travenous injections  was  really  related  to  our  older  method  of  counter- 
irritation  or  "Ableitungs-Therapie,"  has  also  used  gonococcus  vaccine 
and  typhoid  vaccine  in  gonorrheal  complications,  the  latter  especially 
in  gonorrheal  rheumatism.  He  obtained  the  best  clinical  result  with 
the  severest  clinical  reaction,  in  some  instances  the  temperature  reach- 
ing 106°  F. 

Gow  has  also  tried  out  a  diphtheroid  organism  intravenously 
(using  first  a  dosage  of  40  million,  later  200  million)  in  a  case  of 
gonorrheal  arthritis.  There  was  relatively  little  reaction  from  this 
organism,  a  chilly  sensation  was  noted  about  14  hours  after  the  injec- 
tion, a  rise  of  2°  F.  in  the  temperature  2  hours  later,  and  some  head- 
ache. A  leukopenia  followed  the  injection.  The  result  was  not  very 
satisfactory. 


178  PROTEIN  THERAPY 

Konteschweller  in  his  review  of  "pyretotherapy"  states  that  he  has 
obtained  very  satisfactory  results  in  the  treatment  of  gonorrheal 
rheumatism.  He  used  milk,  kephyr  and  peptone  to  elicit  the  reactions. 
Pakauscher  uses  "Fulmargin,"  an  electrically  prepared  colloidal  metal ; 
this  gives  little  general  reaction  but  seems  to  be  useful  nevertheless 
in  the  treatment  of  gonorrheal  complications.  Ullmann  mentions  the 
successful  use  of  milk  in  gonorrheal  arthritis ;  Fraser  and  Duncan  have 
recently  reported  on  the  treatment  of  a  small  series  of  such  arthritic 
cases  treated  with  intravenous  vaccine  injections.  The  vaccines  they 
used  had  been  stored  for  several  months  after  their  preparation,  and 
they  were,  therefore,  probably  more  or  less  detoxicated.  Whether  a  de- 
toxicated  vaccine  has  any  specific  properties  or  not  requires  proof. 
They  suspect  that  a  vaccine  minus  its  endotoxin  consists  simply  of  non- 
specific proteoses  in  a  colloidal  form.  The  injection  of  these,  possibly 
nonspecific  constituents,  would  seem  to  have  caused  the  production 
of  specific  antibodies.  Clinically  they  seemed  to  get  the  same  result 
from  injections  of  T.A.B.  vaccine  as  from  a  gonococcus  or  mixed 
vaccine.  The  chief  reason  for  using  a  gonococcus  vaccine  was  that 
a  supply  was  available,  and  its  use  afforded  a  great  facility  for 
graduating  dosage.  Freshly  prepared  typhoid  vaccine  often  causes  so 
severe  a  reaction  that  they  would  not  risk  giving  it  intravenously. 
Injections  of  endotoxins  always  produce  toxic  symptoms  with  but  lit- 
tle or  no  increase  of  antibodies.  Marked  improvement  followed  in 
all  of  the  fifteen  cases  treated.  No  benefit  seemed  to  result  from  an 
injection  that  was  not  followed  by  pyrexia.  At  the  time  treatment 
was  commenced,  the  patients  were  extremely  debilitated  with  a 
rather  fast  and  weak  pulse,  which  was  easily  accelerated.  The  in- 
jections were  all  intravenous.  The  size  of  the  doses  used  compares 
favorably  with  the  doses  recommended  by  Thomson  for  his  detoxi- 
cated vaccine.  The  largest  dose  of  gonococci  was  2,000  millions. 

The  myositis  of  gonorrheal  origin  has  been  favorably  influenced 
by  intravenous  injections  of  "arthigon"  by  Sachs  while  Reichmann 
has  described  a  favorable  influence  of  collargol  injections  in  the  treat- 
ment of  gonococcus  endocarditis. 

Local  Injections. — The  use  of  milk,  recommended  by  Muller  and 
Weiss,  has  been  quite  extensive  not  only  for  intragluteal  injection 
and  systemic  reactions  (Gellis  and  Winter)  but  for  local  injection  in 
or  about  the  complication.  Weiss  has  treated  a  number  of  cases 
of  epididymitis  in  this  manner,  injecting  from  5tolOc.c.  of  milk  sub- 
cutaneously  in  the  scrotal  skin,  and  obtained  excellent  results. 

This  treatment  by  local  injections  about  the  site  of  the  lesion  was 
commenced  by  R.  Muller  who  observed  that  if  serum  was  so  injected 
it  improved  localized  disease  processes.  Sandek  then  treated  some 
100  cases  of  gonorrheal  complications  with  this  method  and  obtained 
excellent  results.  The  analgesia  following  the  injections  was  aston- 
ishing. 


GONORRHEA  AND  ITS  COMPLICATIONS  179 

Sandek  found  that  if  he  injected  salt  solution  or  potassium  iodid 
in  from  1  to  5%  solution  he  obtained  results  that  were  similar  in 
many  respects.  There  was  of  course  no  general  systemic  reaction 
when  the  treatment  was  carried  out  in  this  manner. 

Eisel  has  continued  observations  on  this  method  of  local  injections 
of  physiological  salt  solution  and  has  reported  on  30  cases  in  which 
from  10  to  15  c.c.  of  physiological  salt  solution  were  injected  between 
the  scrotum  and  the  tunica  vaginalis.  He  states  that  the  pain  was 
lessened  very  promply  and  resorption  of  the  inflammatory  exudate 
facilitated  in  all  of  the  cases  of  epididymitis  so  treated. 

Other  observers  have  treated  gonorrhea  and  gonorrheal  complica- 
tions with  tuberculin  (E.  F.  Miiller)  and  with  turpentine  injections. 
Piirckhauer,  who  has  tried  the  latter  in  acute  urethritis,  considers  such 
injections  of  value  as  adjuvants  but  not  useful  in  bringing  about  com- 
plete recovery  from  the  acute  infection,  his  experience  coinciding 
therefore  with  that  reported  with  the  use  of  the  other  related  agents. 
Karo  has  also  used  turpentine  injections  in  gonorrheal  complications, 
adding  a  small  amount  of  eucupin  to  the  dose  to  lessen  the  local  pain 
that  follows  when  only  turpentine  is  injected.  The  largest  series 
treated  in  this  manner  is  that  of  Krebs  who  has  treated  several  hun- 
dred cases  of  acute  and  chronic  gonorrhea,  with  particularly  good  re- 
sults in  the  severer  infections.  According  to  his  report  the  course 
of  the  acute  disease  was  shortened  and  complications  lessened.  In- 
jections were  given  every  three  to  five  days;  after  the  second  injec- 
tion local  treatment  was  commenced  with  choleval  or  with  potassium 
permanganate.  While  he  considers  that  every  case  should  have  local 
treatment,  the  general  treatment  with  the  turpentine  injections  had 
a  marked  effect  in  lessening  the  pain  and  the  secretion  after  a  very 
short  time. 

Reenstierna  has  made  use  of  a  combined  specific  and  nonspecific 
method  of  treating  the  closed  gonorrheal  complications.  He  injects 
not  only  a  specific  antigonococcus  serum  but  with  it  a  typhoid  vaccine 
to  give  the  general  reaction.  With  this  combined  method  he  claims 
to  have  obtained  very  satisfactory  results. 

Franzmeyer  has  claimed  good  results  in  the  treatment  of  acute 
gonorrhea  by  using  intravenous  injections  of  collargol  combined  with 
local  treatment.  Sommerfeld,  who  treated  42  men  and  10  women 
ill  with  acute  gonorrhea  with  collargol  intravenously,  did  not  find  the 
results  as  satisfactory  as  local  therapy.  Cohn  has  reported  the  treat- 
ment of  86  men  of  whom  only  13  proved  refractory  to  the  nonspecific 
therapy.  Weber,  too,  has  reported  that  as  an  adjuvant,  the  intravenous 
injection  of  colloidal  metals  is  of  benefit  in  the  treatment  of  acute 
gonorrhea.  Nuclein  has  also  been  used  (Boas)  while  Brown  has  re- 
ported on  results  with  normal  horse  serum  as  well  as  diphtheria  anti- 
toxin. He  observed  that  the  dose  of  normal  serum  which  had  to  be 
used  to  secure  results  was  much  larger  than  the  diphtheria  antitoxin. 


180  PROTEIN  THERAPY 

On  the  other  hand,  Riecke  has  reported  that  he  has  never  observed 
a  single  recovery  of  an  acute  gonorrhea  following  the  fever  therapy 
unless  local  treatment  was  instituted.  From  our  present  knowledge  of 
infections  of  the  mucous  membranes  it  is  probable  that  in  acute  infec- 
tions nonspecific  therapy  has  a  limited  field  as  an  adjuvant  to  local 
therapy,  while  in  the  gonorrheal  complications  it  finds  a  much  wider 
and  more  useful  application. 

Buboes. —  Stark  and  Odstrcil  began  the  use  of  milk  injections  in 
the  treatment  of  buboes,  which,  like  the  other  gonorrheal  complications, 
seem  to  respond  very  well  to  this  form  of  therapy.  Miiller  and  Weiss 
had  already  noted  that  certain  gonorrheal  complications  yielded  quite 
readily  to  the  milk  injections  and  Miiller  himself  has  published  some 
25  cases  of  buboes  treated  by  means  of  milk  injections.  With  one 
exception  all  of  these  (17  early  cases,  7  older  ones)  were  cured  with- 
out surgical  incision.  Miiller  gave  injections  of  milk  every  3-4  days 
using  from  5-6  c.c.  of  milk  for  the  purpose.  Usually  the  local  reaction 
reached  its  maximum  in  about  8-9  hours  when  the  greatest  pain  was 
noted,  after  which  the  part  affected  became  analgesic.  In  the  treat- 
ment of  the  old  cases  an  average  of  5  injections  of  milk  were  made;  in 
the  earlier  cases  3  or  4  injections  sufficed  for  a  complete  cure.  Tross- 
arello  has  also  reported  on  the  successful  use  of  milk  injections  in 
the  treatment  of  buboes.  In  15  cases  the  injections  practically  aborted 
the  lesions. 

Schneller  treated  but  two  cases  with  milk  injections,  but  both  made 
complete  recoveries  without  surgical  intervention. 

Guszmann  has  reported  that  milk  injections  are  followed  by  ex- 
cellent results  in  the  treatment  of  soft  chancres,  while  Antoni  using 
aolan  (casein)  obtained  equally  good  results  in  soft  chancres  and 
buboes. 

Reichenstein  used  milk  in  both  buboes  and  epididymitis.  The 
buboes  usually  softened  rapidly  and  were  then  incised;  the  epidi- 
dymitis also  showed  retrogression  shortly  after  the  treatment  was 
commenced.  No  more  than  three  injections  were  ever  necessary. 

Almkvist  treated  8  cases  of  buboes  with  turpentine  with  tuberculin 
and  with  nuclein  injections.  The  cases  all  made  a  rapid  and  complete 
recovery. 

Kraus,  on  the  other  hand,  treated  20  cases  of  gonorrhea  (acute) 
with  milk  injections  (5  to  8  c.c.)  without  much  apparent  benefit. 
In  7  cases  there  was  no  general  reaction  to  the  injections;  the  focal 
reaction  likewise  was  not  marked  in  any  of  the  cases.  Grabisch, 
using  turpentine  injections,  obtained  favorable  results  in  gonorrheal 
complications  such  as  buboes,  cystitis  and  even  pyelitis. 

Karo,  who  has  recently  employed  "terpichin,"  a  turpentine  prepara- 
tion combined  with  quinin,  has  reported  on  the  use  of  this  agent  in 
a  very  large  series  of  cases.  In  acute  gonorrhea  he  has  used  it  in 
combination  with  the  usual  local  treatment  but  considers  that  the 


GONORRHEA  AND  ITS  COMPLICATIONS  181 

injections  shorten  the  course  of  the  disease  as  well  as  prevent  com- 
plications. The  ordinary  complications  are  relieved  in  a  very  short 
time  and  even  the  arthritis  is  very  favorably  influenced. 

Provocative  Reaction.  — In  a  recent  paper  Miiller  has  discussed 
a  subject  that  is  of  considerable  and  increasing  importance  in  the 
genito-urinary  field,  namely  the  provocative  reaction  in  male  urethral 
gonorrhea.  While  I  have  referred  to  it  more  fully  in  the  chapter  on 
focal  reactions,  a  note  of  it  should  be  made  at  this  place. 

We  are  familiar  with  the  effect  of  alcoholic  excess  on  the  course 
of  an  acute  gonorrhea.  Many  of  our  modern  therapeutic  methods 
are  frequently  followed  by  a  similar  provocation  of  a  latent  gonor- 
rhea (such  as  the  use  of  bougies,  Kollmann  dilatation,  silver  salts  in 
higher  concentration,  hydrogen  peroxid,  etc.),  and  their  use  is  fol- 
lowed by  an  increase  in  the  discharge  and  the  finding  of  organisms 
in  the  smear.  On  examination  it  is  observed  that  the  copious  leu- 
kocytic  discharge  consists  of  fresh  leukocytes,  not  old  forms  which 
may  have  been  present  in  the  focus  for  a  longer  period  of  time.  They 
are  the  result  of  a  myelotic  stimulation  that  is  induced  by  the  re- 
action when  the  gonococci  are  stirred  up  at  the  focus,  and  are  there- 
fore to  be  regarded  in  the  nature  of  a  defensive  reaction.  Every  pro- 
cedure that  first  lowers  the  resistance — either  locally  as  with  the  vari- 
out  traumas  mentioned,  or  generally,  as  after  alcohol,  after  an  inter- 
current  disease,  after  a  nonspecific  vaccination — is  followed  by  this 
myelotic  stimulation  and  an  increase  in  the  discharge.  If  provoked 
by  a  local  method  new  paths  may  be  opened  for  the  spread  of  the  in- 
fection, and  it  therefore  entails  an  element  of  danger.  Miiller  noticed 
that  the  intracutaneous  (first  used  by  Hecht)  injection  of  aolan 
(casein)  was  followed  by  a  marked  effect  on  the  infections  of  the 
mucous  membranes  and  in  applying  this  to  gonorrhea  found  that  in 
from  6  to  8  hours  after  the  injection  there  was  noted  a  distinct  itch- 
ing of  the  urethra,  followed  by  an  increased  flow  of  pus  and  usually 
the  possibility  of  demonstrating  the  presence  of  the  organism  within 
24  hours  after  the  injection.  Nevermann  has  applied  this  reaction 
with  success  in  women. 

Adnexal  Inflammation. — It  will  be  recalled  that  Kraus  in  his  early 
work  with  heterovaccines  found  that  he  could  definitely  terminate 
the  fever  of  puerperal  sepsis  in  a  number  of  cases  when  colon  vaccine 
was  injected  intravenously.  Since  that  time  a  number  of  observers 
have  been  interested  in  treating  not  only  such  cases,  but  adnexal 
inflammation  in  women  due  to  other  causes — venereal  infection,  tuber- 
culosis, etc.  For  this  purpose  several  methods  have  been  used 
— milk  injections,  salt  injections,  colloidal  metals,  turpentine  injec- 
tions, etc.  In  general  it  may  be  stated  that  in  this  form  of  inflamma- 
tion the  single  shock  dose — whether  milk  or  vaccine  or  colloidal 
metal — is  less  satisfactory  than  any  form  which  is  carried  out  over  a 
longer  period  of  time  and  is  milder  in  character.  Considering  the 


182  PROTEIN  THERAPY 

extent  of  the  inflammatory  changes  and  their  peculiar  character  this 
result  might  be  anticipated.  In  general  it  may  be  stated  that  the 
findings  that  hold  true  for  venereal  infection  in  the  male  hold  true  in 
the  female,  that  is,  that  the  acute  infection,  either  cervical,  urethral  or 
uterine,  is  not  influenced  very  much  by  this  form  of  therapy,  that 
the  complications,  on  the  other  hand,  are  remarkably  amenable  to 
treatment  and  at  times  give  exceptionally  good  results. 

Menzi  treated  117  cases  with  collargol  injections,  using  from  2 
to  10  c.c.  of  a  2%  solution  every  two  days.  He  states  that  of  34 
cases  of  urethral  gonorrhea,  acute  and  subacute,  23  became  nega- 
tive bacteriologically.  Of  7  cases  of  chronic  urethritis,  all  became 
negative.  Of  24  cervical  infection  23  became  negative.  Two  cases 
of  uterine  infection  were  unchanged.  Lux,  who  obtained  good  re- 
sults in  gonorrheal  complications  with  injections  of  collargol,  obtained 
negative  results  in  acute  infections,  and  Sommerfeld,  too,  did  not  see 
that  in  acute  cases  the  treatment  was  as  efficacious  as  local  treatment. 
Kleemaiin  treated  51  patients  of  this  type  with  injections  of  2% 
collargol;  of  these  11  were  cured,  20  improved,  while  20  were  not  altered 
clinically.  Kleemann  is  of  the  impression  that  the  injections  shorten 
the  course  of  the  disease  and  when  combined  with  local  treatment  are 
of  manifest  assistance.  Infections  of  the  uterus  were  also  found  by 
him  to  be  refractory.  Konteschweller  recommends  "pyretotherapy," 
produced  by  any  of  the  common  nonspecific  agents,  as  of  value  in 
tubal  inflammation. 

Gerstein,  working  at  the  clinic  at  Halle,  had  used  milk  injections, 
but  the  general  effects  were  at  times  rather  unpleasant  so  that  Kauert 
first  used  aolan  (casein  preparation).  With  this  he  treated  16  cases 
of  pyosalpinx.  Only  one  case  reacted  with  a  temperature  rise  and 
there  was  practically  no  leukocytic  reaction.  In  these  cases  Kauert 
saw  very  little  clinical  change.  Not  obtaining  any  results  with  the 
aolan  Kauert  turned  to  milk  injections,  but  here,  too,  his  results  were 
not  successful.  This  corresponds  to  the  results  reported  by  Chiaudano. 

Trossarello  gave  parenteral  injections  of  milk  in  the  treat- 
ment of  forty-five  cases  of  gonococcus  infection  and  in  fifteen  cases 
of  venereal  bubo.  In  the  apyretic  there  is  an  interval  of  two  or  three 
hours  before  the  chill  follows  the  injection,  and  this  allows  ambula- 
tory treatment  as  the  patients  are  able  to  reach  home  before  it.  No 
benefit  was  apparent  in  the  cases  of  urethritis,  prostatitis,  epididymitis 
and  arthritis,  but  in  ovarian  and  tubal  disease  marked  benefit  was 
realized.  All  were  improved,  some  after  a  single  injection.  His  re- 
sults in  these  twenty  cases  of  adnexitis  surpassed,  he  says,  those  ob- 
tained with  specific  vaccines  or  antiserums ;  the  pain  subsided  promptly 
even  before  any  objective  improvement  was  apparent.  He  injected 
into  the  buttocks  5  or  10  c.c.  of  ordinary  milk,  at  intervals  of  three 
or  four  days,  to  a  total  of  five  injections.  The  febrile  reaction  seems 


GONORRHEA  AND  ITS  COMPLICATIONS  183 

to  be  the  main  factor;  the  best  results  were  noted  in  the  patients 
that  presented  the  strongest  reactions. 

Arweiler,  working  with  Lindig  on  casein  injections  (intravenous), 
reports  satisfactory  results  in  adnexal  inflammations,  the  tumor  masses 
showing  definite  regression  and  the  patients  a  general  improvement  in 
condition. 

Schonfeld  tried  the  method  recommended  by  v.  Szily  and  Stransky 
(salt  abscess)  in  36  cases  of  acute  and  subacute  gonorrheal  infections 
in  women.  They  obtained  very  poor  results;  only  those  made  a  re- 
covery in  whom  abscess  formation  occurred.  The  method  is  painful 
and  certainly  not  to  be  recommended. 

More  recently  a  number  of  clinicians  have  tried  the  method  of 
turpentine  injection  with  evidently  more  success.  Fuchs,  as  well  as 
Schubert,  while  in  military  service,  had  tried  intramuscular  turpentine 
injections  in  suppurating  wounds  without  any  effect  (where  we  al- 
ready have  a  large  suppurating  surface  from  which  -necrotic  products 
are  being  absorbed,  this  result  is  to  be  anticipated),  but  found  that 
when  used  in  adnexal  inflammation  he  obtained  quite  remarkable  re- 
sults. Zoeppritz  and  Kleeman  had  previously  reported  a  fairly  large 
series  of  cases  and  Fuchs  reports  30  gynecological  cases  treated  by  the 
injection  of  0.5  c.c.  (of  4  parts  of  turpentine,  0.2  part  of  eucupin  and 
16  parts  of  olive  oil)  every  4  days  intramuscularly.  The  site  of  the 
injection  was  the  axillary  line  just  below  the  crests  of  the  ilium,  in- 
jection being  made  very  deep. 

Kleemann's  cases  numbered  over  60  and  included  all  varieties  of 
adnexal  inflammation.  In  this  series  36  were  completely  cured,  21 
improved  and  3  were  not  improved.  He  observed  that  the  fever  as 
a  rule  diminishes  after  a  short  time  and  the  size  of  the  adnexal  tumor 
decreased  until  in  many  instances  it  was  no  longer  possible  to  palpate 
the  mass.  He  used  turpentine  with  a  small  amount  of  novocain  to 
prevent  local  pain  after  the  injection. 

The  cases  selected  were  bilateral  adnexal  inflammations,  with  the 
tumor  masses  varying  in  size  from  2  to  10  cm.  in  diameter,  with  oc- 
casional temperature,  menstrual  disturbance — pain,  bleeding,  etc.  In 
five  of  the  cases  a  chronic  gonorrhea  was  manifest.  The  results  of  the 
treatment  were  very  satisfactory,  convalescence  being  established  much 
sooner  than  with  the  ordinary  local  or  expectant  treatment.  Not  only 
was  the  local  tumor  mass  reduced  in  size — Fuchs  states  that  the  large 
masses  reduced  in  two  weeks'  time  to  the  size  of  a  walnut — but  the  pa- 
tients felt  better  in  general  and  the  appetite  was  stimulated.  Occa- 
sionally a  temperature  reaction  of  from  1°  to  2°  C.  was  observed  fol- 
lowing the  injection;  these  cases  gave  the  most  striking  clinical  im- 
provement. In  no  case  did  he  have  any  untoward  effect  or  find  any 
injury  from  the  treatment;  in  over  200  injections  there  was  no  abscess 
formation. 

According  to  Fuchs  the  treatment  is  of  very  definite  gynecological 


184  PROTEIN  THERAPY 

value,  even  in  the  treatment  of  early  adnexal  inflammation  accom- 
panied by  acute  symptoms  and  much  pain  and  profuse  hemorrhage. 
The  pain  diminishes  after  the  second  injection,  menstruation  becomes 
normal  after  the  next  period  and  the  adnexal  swelling  is  reduced.  The 
fact  that  these  results  can  be  achieved  with  an  ambulatory  treatment  is 
of  further  advantage. 

Sonnenfeld  has  also  reported  on  115  cases  of  gonorrheal  as  well  as 
nongonorrheal  adnexal  inflammatory  lesions  treated  with  turpentine 
injections.  He  considers  the  method  of  tremendous  advantage  in 
the  conservative  treatment  of  inflammatory  conditions  of  this  type. 

Hellendall  states  that  when  on  the  basis  of  thirty  cases  Zoppritz 
demonstrated  this  method  recently  before  the  Verein  der  Aerzte  at 
Diisseldorf,  no  adherents  championed  it  during  the  discussion  that  fol- 
lowed, while  Pankow  presented  two  series  of  cases,  one  treated  with 
and  one  without  turpentine,  and  emphasized  that  the  results  indi- 
cated that  there  was  no  difference  between  the  old  conservative  treat- 
ment and  the  turpentine  treatment  so  far  as  the  final  effect  was  con- 
cerned. In  Hellendall's  own  case,  that  of  a  young  woman  of  19,  the 
ineffectiveness  of  turpentine  injections  was  shown  by  a  later  operation, 
although  it  was  a  case  in  which  good  effects  should  have  been  appar- 
ent, if  ever.  Kronnenberg  is  also  of  the  opinion  that  the  turpentine 
injections  are  without  influence  on  the  course  of  adnexal  inflammation. 

Hinze  reports  205  cases,  35  of  which  came  to  operation;  65  were 
treated  by  the  usual  conservative  methods  and  105  with  turpentine. 
He  injected  0.5  c.c.  of  a  mixture  of  0.1  gm.  of  turpentine  oil  and  0.4 
gm.  of  olive  oil,  in  the  posterior  axillary  line  from  two  to  three  finger- 
breadths  below  the  crest  of  the  ilium.  The  long  cannula  prevents 
the  fluid  being  ejected  into  muscle  or  subcutaneous  tissue,  which  in- 
creases the  pain  unnecessarily.  In  addition,  in  most  cases,  moist  heat 
and  hot  air  or  hot-water  treatment  were  employed.  The  discomfort 
following  the  injections  was  not  severe  and  usually  subsided  in  from 
four  to  five  hours,  but  in  several  cases  the  pain  lasted  from  three  to 
four  days,  sometimes  radiating  into  the  leg  on  the  same  side.  In  8 
of  the  cases  of  pyosalpinx  either  a  cure  or  marked  improvement  was 
effected.  The  results  were  very  favorable  in  the  52  mild  cases.  As 
a  rule  these  cases  could  be  dismissed  as  cured  in  from  two  to  three 
weeks.  In  the  chronic  cases,  the  pains  usually  disappeared  after  a 
few  injections,  and  when  the  patients  were  dismissed  in  three  or  four 
weeks  the  tumors  had  decreased  considerably  in  size.  Hinz's  judg- 
ment, therefore,  is  that  turpentine  injections  constitute  progress  in 
conservative  treatment  of  affections  of  the  adnexa.  However,  that 
recurrences  are  not  uncommon  goes  without  saying. 

Other  observers  have  used  autoserotherapy  (Ishikawa)  and  Hasen- 
beia  has  used  injections  of  sugar  solutions. 


CHAPTER  XI 

INFECTIOUS  DISEASES 

ANTHRAX 

The  treatment  of  anthrax  by  means  of  injections  of  normal  beef 
serum  is  a  procedure  inaugurated  by  Kraus  and  his  associates,  and 
has  been  discussed  by  them  in  a  series  of  articles.  They  use  beef 
serum  twice  heated  to  56°  C.  for  30  minutes  and  inject  from  30  to 
50  c.c.  or  more  intravenously  or  intramuscularly.  According  to  Kraus' 
recent  address,  over  380  cases  have  been  treated  by  him  with  this 
method  with  a  mortality  of  less  than  6.2%,  as  contrasted  with  the 
mortality  of  about  10%  with  expectant  treatment.  The  injections 
are  made  repeatedly,  usually  in  12  hour  intervals,  although  as  a  rule 
not  more  than  three  injections  are  necessary.  Serum  sickness  has 
seldom  been  observed. 

Solari  reports  the  results  in  6  cases,  all  of  which  recovered.  Langon 
treated  13  with  similarly  satisfactory  results.  Lignieres,  however,  was 
not  able  to  confirm  these  findings. 

Recently  several  experimental  studies  have  been  reported  dealing 
with  the  problem,  including  those  of  Turro,  of  v.  Hutyra  and  Maninger, 
Gerlach,  Kraus  and  Beltrami  and  of  Kolmer,  Wanner  and  Koehler. 
The  latter  observers  were  able  to  determine  some  degree  of  bacteri- 
cidal property  in  the  normal  beef  serum,  but  hardly  sufficient  to  ac- 
count for  the  marked  clinical  effect  induced  by  the  serum  injections. 
Heretofore  it  had  been  assumed  by  a  number  of  clinicians  that  the 
effect  of  the  beef  serum  might  be  due  to  the  content  of  natural  anti- 
anthrax  amboceptors  in  the  serum  of  the  animals  used  for  injection, 
because  of  the  possibility  of  a  degree  of  immunity  present  in  the 
serum  of  cattle  where  anthrax  is  prevalent. 

v.  Hutyra  and  Maninger's  tabulated  results  show  that  no  pro- 
tection was  afforded  rabbits  inoculated  with  anthrax  by  treatment 
with  normal  beef,  horse  or  sheep  serum. 

DIPHTHERIA  AND  DIPHTHERIA  CARRIERS 

One  of  the  most  remarkable  reports  concerning  the  application  of 
nonspecific  methods  in  therapy  has  been  that  of  Bingel,  which  has 
created  considerable  discussion  because  it  throws  doubt  on  the  spe- 
cific value  of  our  most  widely  used  and  most  representative  of  specific 
sera,  namely  diphtheria  antitoxin. 

Bingel  treated  471  cases  of  diphtheria  with  diphtheria  antitoxin 

185 


186  PROTEIN  THERAPY 

and  466  alternating  cases  with  empty  horse  serum— that  is,  normal 
horse  serum  which  contained  no  antitoxin.  The  results  as  far  as 
could  be  judged  in  the  two  series  showed  no  difference  in  the  mortality, 
in  the  duration  of  the  illness,  or  in  the  number  of  complications. 
As  a  matter  of  fact  Bertin  is  said  to  have  used  injections  of  normal 
serum  as  early  as  1895  in  diphtheria,  and  Roily  as  well  as  v.  Striimpell 
also  employed  "empty"  serum.  In  1912  Lorey  again  called  attention 
to  the  subject. 

Attention  is  called  to  Bingel's  paper  not  because  it  describes  a 
desirable  mode  of  procedure  that  is  to  be  commended,  but  because 
of  its  theoretic  and  practical  importance.  There  can  be  no  doubt 
that  specific  antitoxin  will  exhibit  incomparable  superiority  over  nor- 
mal horse  serum  both  in  practical  therapeutic  application  and  in  ani- 
mal experimentation.  But  in  practice  the  observation  of  Bingel  has 
been  confirmed,  even  if  not  in  a  large  series,  by  Dorn  and  by  Meyer. 
Klotz  has  recently  reviewed  the  entire  subject. 

There  has  been  an  often  expressed  observation  among  a  number 
of  clinicians  during  more  recent  years  that  the  modern  highly  con- 
centrated diphtheria  antitoxin  does  not  always  give  the  same  satis- 
factory results  that  our  older,  less  concentrated  preparations  did. 
Of  the  older  preparations  larger  doses  of  serum  had  to  be  injected. 
The  work  of  Bingel  makes  clear  the  basis  for  this  conviction.  That 
is,  we  are  dealing  in  diphtheria  antitoxin  with  two  factors  that  are  of 
therapeutic  value,  the  specific  antitoxin  content  and  the  nonspecific 
stimulating  property  of  the  serum  proteins.  The  more  highly  con- 
centrated the  preparation,  the  less  of  the  nonspecific  element  will  be 
retained.  This  is  probably  the  reason  that  the  more  modern  serums 
have  at  times  seemed  followed  by  less  therapeutic  effect  than  the  for- 
mer preparations.  As  a  matter  of  fact  when  some  of  the  older  litera- 
ture is  reviewed  one  finds  observations  concerning  the  temporary  rise 
in  temperature  following  diphtheria  antitoxin  injections,  as  well  as 
the  temporary  leukopenia  and  the  later  leukocytosis  that  we  now 
recognize  as  part  of  the  phenomena  that  follow  after  the  various 
nonspecific  injections  (Ewing). 

A  number  of  investigators  have  repeated  BingePs  method,  using 
the  method  of  toxin  neutralization  in  guinea  pigs.  Calhoun,  for  in- 
stance, as  well  as  Kraus  and  Sordelli,  found  a  slight  protection  with 
normal  horse  serum;  other  observers  have  found  little  or  no  protec- 
tion. The  lack  of  confirmation  in  animal  work  does  not,  however, 
rule  out  a  therapeutic  effect  in  human  diphtheria.  Liidke  has  for 
instance  treated  15  cases  of  diphtheria  in  adults  with  albumoses.  (2-3 
injections  of  from  3-5  c.c.  of  a  10%  solution.)  The  therapeutic  effects 
were  quite  comparable  to  those  obtained  with  specific  serum  therapy. 
In  7  cases  the  first  injection  was  followed  by  a  complete  disappearance 
of  the  diphtheritic  membrane  and  the  return  of  the  temperature  curve 
to  normal  within  24  hours.  In  three  cases  in  which  a  stenosis  already 


INFECTIOUS  DISEASES  187 

existed  the  injections  were  followed  by  an  increase  in  the  swelling  and 
the  stenotic  symptoms,  the  usual  effect  of  nonspecific  injections  on  local 
inflammatory  processes.  In  5  cases  there  was  no  apparent  effect  on 
the  disease. 

Paschen  has  used  milk  injections  to  free  diphtheria  carriers  of 
their  throat  infection.  Of  54  cases  37  were  free  in  from  4  to  6  days, 
7  in  14  days,  while  in  10  cases  there  was  no  effect  of  the  injection 
on  the  throat  culture.  In  emphasizing  the  fact  that  the  high  fever 
is  one  of  the  factors  that  aids  in  overcoming  the  condition,  Paschen 
points  out  the  fact  that  of  these  10  refractory  cases  5  did  not  react 
with  any  fever  to  the  milk  injections. 

Miiller  has  also  reported  that  nonspecific  injections — milk  and 
casein — are  effective  in  ridding  the  mucous  membranes  of  the  throat 
and  nasal  passages  of  diphtheria  infection  in  the  case  of  chronic  car- 
riers. 

BACILLARY  DYSENTERY 

The  war  with  its  attendant  epidemics  of  dysentery  both  in  the 
military  forces  and  in  the  civilian  populations  afforded  European 
clinicians  considerable  opportunity  to  study  not  only  the  prophy- 
laxis but  the  therapeusis  of  the  disease  as  well,  and  we  now  have 
reports  available  from  a  number  of  sources.  Among  them  Nolf  has 
published  several  papers  which  are  available  in  the  American  litera- 
ture dealing  with  both  specific  and  nonspecific  intravenous  therapy; 
Adler  was  perhaps  the  first  to  report  on  the  use  of  milk  injections; 
Holler,  in  his  large  series  of  infectious  diseases  treated  with  deutero- 
albumose  injections,  has  included  50  dysentery  cases  and  Dollken  has 
reported  a  number  treated  with  milk  injections. 

Inasmuch  as  Nolf's  experience  was  quite  extensive,  at  first  with 
specific  serum  therapy,  then  with  vaccines  subcutaneously  admin- 
istered and  later  with  intravenous  bacteriotherapy,  it  may  be  of  in- 
terest to  quote  extensively  from  his  recent  paper. 

"The  treatment  of  ulcerative  dysentery  gave  us  only  temporary  results 
so  long  as  we  had  recourse  to  the  methods  of  the  books.  Specific  sero- 
therapy proved  futile.  Therefore,  because  of  the  inefficacy  of  these  methods, 
we  had,  toward  the  end  of  the  epidemic  of  1917,  employed  vaccinotherapy 
in  the  chronic  cases  that  remained.  When  possible  to  isolate  a  dysenteric 
germ  from  the  intestine,  we  made  and  employed  an  autogenous  vaccine; 
otherwise  we  used  a  vaccine  of  a  Flexner  bacillus  type  made  from  a  gelose 
culture  killed  by  heat.  At  this  time  the  vaccine  was  administered  subcu- 
taneously, in  progressively  increasing  doses,  the  initial  dose  being  usually 
10,000.  To  obtain  the  desired  result  it  was  necessary  to  raise  the  dose 
frequently  to  from  5  to  10  billion.  These  large  amounts  of  sterilized  cul- 
ture are  regularly  well  tolerated,  though  often  during  from  twelve  to 
twenty-four  hours  after  the  injections,  one  observes  a  little  fever,  headache 
and  lassitude,  with  more  frequent  and  less  consistent  stools,  sometimes 


188  PROTEIN  THERAPY 

slight  colic,  and  at  the  site  of  injection  a  little  infiltration  with  moderate 
pain.  All  these  sequela  soon  pass  away  and,  as  a  rule,  disturb  the  patient 
but  little. 

"VACCINOTHERAPY  IN  OLD  CHRONIC  CASES 

"In  the  winter  of  1917-1918,  we  still  were  receiving  cases  of  chronic 
dysentery  of  which  the  onset  dated  back  several  months  or  several  years. 
We  applied  the  same  treatment,  but  with  this  difference,  namely,  that  the 
initial  dose  was  regularly  a  million  germs,  and  that  the  dose  was  raised 
progressively  up  to  from  5  to  10  billion.  The  results  obtained  continued  to 
be  favorable.  In  every  case  the  general  condition  was  improved,  and  the 
intestinal  symptoms  steadily  decreased.  In  the  majority,  the  cure  was  com- 
plete and  definite.  At  times  there  seemed  to  be  complete  cure  at  the  end 
of  the  treatment,  but  at  a  later  period  the  symptoms  returned.  In  some 
cases  the  stools,  although  regular  and  only  one  or  two  a  day  and  without 
blood  and  mucus,  yet  remained  soft,  and  there  persisted  a  little  intestinal 
instability  and  discomfort. 

"We  should  probably  have  continued  the  subcutaneous  method  of  ad- 
ministration of  the  vaccine,  had  we  not,  in  other  affections,  particularly 
bacteriuria  due  to  the  colon  bacillus  or  the  staphylococcus,  observed  that 
the  intravenous  method  of  administration  was  more  efficacious  and  more 
rapid  in  its  effects.  We  therefore  began  the  administration  of  the  vaccine 
by  the  intravenous  route  in  bacillary  dysentery, 

"THE  INTRAVENOUS  METHOD  IN  ACUTE  DYSENTERY 

"We  applied  the  treatment  not  only  to  those  with  confirmed  ulcerative 
dysentery,  but  also  to  all  those  in  whom  the  course  of  the  disease  made 
one  fear  the  development  of  the  ulcerative  form,  that  is  to  say,  in  every 
case  in  which,  after  one  week,  a  dietetic  and  drug  treatment  had  not 
brought  about  a  cure,  or  at  least  promise  of  a  speedy  cure. 

"The  doses  were  given  at  four-day  intervals,  the  initial  dose  being  regu- 
larly 10,000  germs,  then  30,000,  then  50,000,  then  1,000,000,  etc.  In  general, 
the  betterment  of  the  patient  did  not  long  delay.  The  fever  dropped  by 
lysis,  with  some  recrudescences  more  or  less  marked  on  the  days  of  the 
vaccine  therapy  and  the  next  day;  and  the  intestinal  symptoms  improved 
coincidently.  In  many  cases  of  moderate  intensity  a  complete  cure  was 
effected  when  the  dose  of  500,000  was  reached.  In  the  more  refractory 
cases,  it  was  necessary  to  push  the  vaccine  up  to  about  10  million. 

"In  fifty-two  cases  treated  in  this  way,  we  had  only  two  deaths.  All  the 
other  patients  left  the  hospital  cured,  except  two  whom  military  necessity 
forced  us  to  send  away  too  soon.  We  have  no  doubt  that  in  these  two 
cases  also  the  continuation  of  the  treatment  would  have  resulted  in  a 
cure  in  a  relatively  short  time.  By  vaccinotherapy  we  were  thus  able  to 
avoid  the  dangerous  tendency  toward  chronicity  which  in  1917  was  pro- 
duced in  a  considerable  number  of  our  patients.  This  last  result  we 
considered  particularly  gratifying. 

"The  complete  record  of  the  epidemic  of  bacillary  dysentery  of  1918  shows 
a  complete  cure,  at  the  latest  in  a  few  weeks'  time,  in  500  cases  except  only 
two  patients  who  died,  and  two  who  had  left  before  the  cure  was  complete. 


INFECTIOUS  DISEASES  189 

"CONCLUSIONS 

t{I  believe  I  am  justified  in  concluding  from  these  observations  that  vac- 
cinotherapy  and  more  especially  vaccination  intravenously  is  the  most  ef- 
fective therapeutic  method  in  bacillary  dysentery  in  its  chronic  forms  and 
in  the  acute  forms  that  show  little  tendency  toward  cure.  It  appears  also 
that  the  method  is  more  efficacious  when  it  is  applied  early.  The  intra- 
venous route  has  the  advantage  that  it  permits  results  from  doses  one- 
thousandth  the  size  of  the  subcutaneous  doses.  Not  having  had  occasion  to 
try  this  method  in  cases  of  Shiga  bacillus  desentery,  it  is  impossible  for  me 
to  speak  of  its  utility  in  this  form  of  dysentery. 

"In  acute  dysentery,  intravenous  vaccinotherapy  cures  quickly  in  cases 
exhibiting  protracted  fever  and  lasting  diarrhea  with  hemorrhagic  and  slimy 
stools,  these  being  the  cases  that  are  refractory  to  other  therapeutic  meth- 
ods, including  serotherapy." 

Of  course,  the  bacteriotherapy  is  not  a  specific  procedure ;  the  same 
effect  can  be  obtained  when  the  reaction  is  produced  by  any  of  the 
other  agents. 

Milk  injections,  first  used  by  Adler  in  dysentery  and  cholera, 
were  also  used  by  Dollken,  who  employed  them  because  of  the  marked 
styptic  effect  following  intramuscular  injections;  he  did  not,  how- 
ever, observe  any  actual  change  in  the  coagulation  time  of  the  blood 
of  dysentery  patients  before  and  after  the  treatment.  It  is  to  be 
assumed  that  in  the  early  stages  of  dysentery  when  hyperemia  and 
engorgement  of  the  mucosa  are  not  yet  pronounced  and  where  we 
are  dealing  merely  with  small  petechial  hemorrhages  and  a  hyper- 
secretion,  the  injections  will  be  followed  with  the  best  clinical  result 
and  this  is  actually  found  to  be  the  case  in  clinical  practice. 

Dollken  injected  5  c.c.  of  milk  intramuscularly  (occasionally  less). 
Sometimes  after  5  or  6  hours  a  definite  focal  reaction  was  to  be 
observed  in  the  form  of  increased  evacuations  containing  more  blood. 
The  recovery  was  very  prompt  after  this  period.  Usually  the  first 
day  after  the  injection  the  blood  was  considerably  less,  even  absent 
in  some  stools.  This  was  observed  to  continue  after  the  second  in- 
jection. Usually  after  5  days  blood  was  no  longer  present.  The 
spasm  of  the  small  bowel  was  almost  always  relieved  after  the  first 
injection;  the  tenesmus  in  4  or  5  hours  after  the  first  injection.  An 
interesting  fact  was  noted  in  regard  to  those  cases  that  had  had  al- 
buminuria.  This  was  invariably  gone  after  the  injection. 

Contrary  to  the  experience  of  Nolf,  Dollken  did  not  observe  much 
effect  on  the  temperature  curve  after  the  milk  injections,  although 
in  some  cases  a  defervescence  was  noticed  after  the  second  injection. 
In  cases  treated  with  specific  sera  and  vaccines  this  same  lack  of  ef- 
fect on  the  temperature  of  course  holds  true. 

In  more  advanced  cases  the  ulceration  does  not  yield  to  treatment 
so  readily.  After  about  5  days,  however,  improvement  is  noted  in 


190  PROTEIN  THERAPY 

the  tenesmus  and  obstipation,  but  the  hemorrhages  are  apt  to  per- 
sist longer.  In  cases  that  have  diphtheritic  membranes  Dollken  ob- 
tained good  results  after  repeated  injections. 

Of  theoretic  interest  was  the  fact  that  in  cured  cases  Dollken  was 
at  times  still  able  to  cultivate  the  causative  organism  (Flexner)  from 
the  stool;  the  agglutination  titer  of  the  patient's  serum,  no  matter 
what  the  clinical  outcome,  was  not  altered  by  the  milk  injections, 
but  after  specific  vaccination  was  increased. 

Deutero-albumose,  tried  in  several  cases  by  Dollken,  was  not  as 
satisfactory.  Holler,  on  the  other  hand,  has  treated  50  cases  of  bac- 
illary  dysentery  (Kraus  and  Shiga)  with  daily  injections  of  deutero- 
albumose  and  in  this  series  had  only  two  deaths. 

Liidke  treated  14  cases  of  severe  dysentery  (12  Shiga  and  2 
Flexner  Type)  with  deutero-albumose  injections  (3  to  6  injections  of 
from  1-2  c.c.  of  a  10%  solution).  Apart  from  absolute  rest  in  bed, 
heating  pads,  and  proper  diet,  there  was  no  other  therapy  used  in 
these  cases.  In  from  3  to  6  days  12  patients  were  markedly  improved 
— the  stools  were  normal  and  free  from  blood  or  mucus,  tenesmus 
had  disappeared  and  the  general  condition  and  appetite  returned  to 
normal  very  rapidly.  In  two  cases,  in  which  an  earlier  effort  with 
serum  therapy  had  been  unavailing,  the  injections  of  deutero- 
albumoses  was  also  without  effect. 

Furno  treated  5  cases  of  hemorrhagic  dysenteriform  colitis,  due  pos- 
sibly to  mixed  infection,  with  intravenous  injections .  of  proteoses 
(10  to  12  c.c.  of  10%  solution).  He  found  that  by  prompt  therapy 
of  this  kind  the  disease  is  arrested  before  it  reaches  the  ulcerative 
stage. 

Reiter  found  on  the  other  hand  that  in  a  small  series  of  cases 
only  one  case  actually  improved.  Schelenz,  using  polyvalent  serum 
and  also  injections  of  dysentery  vaccine,  found  that  while  the  course 
of  the  fever  was  not  altered  very  much,  the  blood  disappeared  from 
the  stool,  the  diarrhea  decreased  and  the  general  condition  of  the 
patient  improved. 

While  specific  serum  has  been  used  by  many  clinicians,  general 
opinion  seems  to  confirm  the  conclusion  of  Nolf  that  it  is  not  of  great 
value  unless  given  in  huge  doses  either  intramuscularly  or  intrave- 
nously and  frequently  repeated.  Pfeiffer  used  100  c.c.  of  polyvalent 
serum  irrespective  of  the  bacteriological  finding  and  gave  five  to  six 
injections;  usually  a  slight  systemic  reaction  would  be  observed  after 
the  injections.  The  size  of  the  dose  necessary  and  the  fact  that  it 
must  be  given  very  early  if  it  is  to  be  useful  at  all  leads  to  the  con- 
clusion that  the  effect  can  only  be  found  in  the  nonspecific  stimula- 
tion by  the  serum,  rather  than  in  any  specific  antibody  content.  Schit- 
tenhelm's  results  would  lead  to  the  same  conclusion,  v.  Scilly  and 
Vertes  made  use  of  this  feature  by  injecting  their  patients  with 
"solusin,"  a  rather  toxic  agent  described  elsewhere,  from  the  use  of 


INFECTIOUS  DISEASES  191 

which  they  claim  to  have  obtained  results  equally  as  satisfactory 
as  from  the  specific  serum  injections. 

ERYSIPELAS 

The  treatment  of  erysipelas  by  means  of  antistreptococcal  serum, 
usually  by  subcutaneous  injections,  is  by  no  means  a  recent  procedure, 
nor  one  concerning  the  value  of  which  an  agreement  has  been  reached 
by  clinicians.  Chantemesse  used  Marmorek  serum  in  some  500  cases 
and  gained  the  impression  that  the  process  of  recovery  was  accelerated. 
After  24  hours  the  swelling,  induration  and  pain  began  to  diminish 
while  within  a  few  hours  after  the  injection  the  general  condition 
of  the  patient  improved.  Jochmann,  who  had  a  considerable  experi- 
ence, concluded  that  where  the  local  inflammation  was  to  be  influ- 
enced, subcutaneous  therapy  was  valueless,  but  that  in  the  severely 
toxic  cases  with  delirium,  rapid  pulse,  etc.,  the  effect  of  the  serum  was 
manifest  in  improving  the  general  condition. 

Since  the  introduction  of  the  intravenous  methods  of  administra- 
tion of  antistreptococcus  serum,  or  with  nonspecific  methods,  one  can 
determine  a  more  marked  effect  on  the  disease,  both  locally  and  in 
the  general  effect  on  the  patient.  Together  with  Jobling  and  Manier 
we  commenced  the  treatment  of  erysipelas  in  1915  with  proteoses  in- 
jected intravenously.  The  results  in  several  cases  have  been  presented 
by  Jobling.  Since  that  time  the  writer  has  had  opportunity  of  ob- 
serving a  series  of  about  15  additional  cases  treated  either  with  prote- 
oses, milk,  or  typhoid  vaccine  and  the  results  have  in  all  cases  been 
very  satisfactory,  indeed  in  some  cases  seemingly  quite  remarkable. 
The  rapid  subsidence  of  the  intoxication,  the  general  improvement  of 
the  sensorium  and  cardiovascular  apparatus  gave  striking  evidence 
of  the  decrease  in  the  intoxication.  The  local  process  is  also  influenced, 
usually  not,  however,  until  there  is  evidence  of  the  systemic  effect  in 
the  euphoria  and  lessening  of  the  toxicity  of  the  patient. 

French  clinicians  have  used  subcutaneous  injections  and  oral  ad- 
ministration of  normal  serum  as  well  as  diphtheria  antitoxin  in  the 
treatment  of  erysipelas  for  a  number  of  years  (Launois,  Darier, 
Apostolleaun,  Pollak  and  Mayweg)  with  some  success,  but  in  recent 
years  the  intravenous  injection  of  such  sera  has  evidently  been  fol- 
lowed by  more  apparent  effects  on  the  course  of  the  disease.  Koller, 
Uhlig,  Basset,  Campani,  Frank  and  Bugolli  report  on  cases  so  treated 
and  Boyksen,  who  used  normal  horse  serum,  treated  a  rather  large 
series.  In  severely  toxic  or  extensive  infection  he  administered  20 
c.c. '  intravenously  together  with  10  c.c.  subcutaneously ;  in  the  milder 
cases  only  10  c.c.  was  given  intravenously. 

The  colloidal  metals  have  also  been  employed,  at  times  with  suc- 
cess. (Eberstadt,  Cholewa,  Capitan,  etc.) 

Holler  calls  attention  to  a  fact  which  we  have  observed  at  vari- 


192  PROTEIN  THERAPY 

ous  times,  namely,  that  intravenous  injections  of  this  kind  may  be 
followed  by  a  very  marked  reaction  on  the  part  of  the  patient,  so 
that  even  relatively  small  doses  may  incite  a  severe  general  reaction. 
Holler  treated  32  cases  of  erysipelas  with  small  daily  injections  of 
deutero-albumose,  all  of  whom  made  a  prompt  and  uncomplicated  re- 
covery. The  reaction  was,  however,  at  times  quite  severe,  in  some 
cases  the  patients  becoming  delirious  for  a  short  period  following  the 
chill.  Nolf  has  described  the  use  of  peptones,  Kraus,  Turnheim 
and  Reichenstein  obtained  satisfactory  results  with  milk  injections 
while  Blumenau  treated  77  cases  with  nuclein  injections.  In  this 
series  the  favorable  effect  was  more  apparent  in  the  general  condi- 
tion of  the  patient  than  on  the  local  process.  Audain  and  Masmon- 
teil  used  sugar  solutions;  Englander  reports  that  following  the  intra- 
venous injection  of  salt  solution — 100  to  150  c.c. — the  temperature 
usually  returned  to  normal  very  promptly;  v.  Szily  and  Schiller  used 
typhoid  vaccine  successfully.  A  number  of  observers  have  obtained 
satisfactory  results  with  either  direct  or  artificial  sunlight.  (Bruce 
and  Hodgson,  Capelle,  Klapp,  etc.) 

Schmidt  has  recently  reported  on  a  series  of  52  cases  treated  with 
milk  injections.  Of  these  44  involved  the  face,  4  the  upper  extremi- 
ties, 3  the  lower  and  in  one  case  the  abdominal  skin  was  involved. 

The  results  were  as  follows: 

Upper    Lower 

Defervescence  Face  Cases  Extremity  Abdomen 

1st  Day  after  injection  ....  27  2  1  1 

2nd     "       "  "       8  2  2 

3rd     "       "  "       ....  4 

Of  the  4  cases  that  did  not  respond  until  the  3rd  day,  one  had  an  angina, 
and  two  had  a  lymphadenitis  colli  (tuberculous). 

The  five  remaining  cases  which  persisted  longer  than  3  days  were  all 
complicated  by  other  infections. 

INFLUENZA 

The  recent  pandemic  of  influenza  gave  opportunity  to  study  the 
effect  of  a  great  variety  of  nonspecific  agents  on  the  clinical  course, 
particularly  of  the  complicating  bronchopneumonia,  and  a  considerable 
literature  has  developed  which  can  only  be  briefly  reviewed  at  this 
time. 

Colloidal  Metals. — Teller  reported  satisfactory  results  with  col- 
largol.  Capitan,  who  treated  321  cases  of  uncomplicated  influenza 
and  208  cases  of  bronchopneumonia  of  influenzal  origin,  used  a  col- 
loidal arsenic  preparation,  which  he  had  previously  found  useful  in 
tuberculosis  and  syphilis.  The  preparation  contained  3  mg.  of  arsenic 
and  2  mg.  of  silver  per  cubic  centimeter,  and  of  this  from  6  to  9 
c.c.  were  injected  either  intramuscularly  or  intravenously.  He  de- 


INFECTIOUS  DISEASES  193 

termined  a  favorable  effect  on  the  pulse  rate  and  the  general  con- 
dition of  the  patient;  the  temperature  usually  declined  in  about  3 
days  after  commencing  the  treatment.  Van  Andel  and  Heymans 
both  used  collargol  in  a  small  series  of  cases  with  favorable  results. 
Hodel  found  both  collargol  and  the  fixation  abscess  useful  in  influ- 
enza. Holden  used  colloidal  silver  and  Richard,  Remond  and  Netter 
have  also  reported  on  the  use  of  similar  metallic  preparations.  Tail- 
lens  treated  some  300  cases  of  influenza  and  complications  with  a 
number  of  different  agents.  Salvarsan  was  not  effective,  euesol  and 
galyl  were  also  found  useless;  colloidal  metals  were  only  useful  in 
very  large  doses. 

Wachter  used  collargol  in  influenza  and  obtained  good  results  if 
it  was  administered  sufficiently  early.  In  the  pleurisy  following 
pneumonias  it  was  also  useful.  He  recommends  care  if  there  is  any 
nephritis  present  because  he  observed  that  several  cases  had  a  recur- 
rence of  casts  and  albumin  in  the  urine  after  the  collargol  injections. 

Witte  also  recommends  such  intravenous  injections  if  they  can 
be  given  early  enough. 

The  fixation  abscess  and  turpentine  injections  (collobiase)  seem 
to  have  been  used  with  considerable  success.  Taillens  reports  that 
injections  of  turpentine  gave  him  better  results  than  the  other  agents 
that  he  employed  (see  above).  He  used  it  in  38  cases.  Netter,  who 
treated  230  simple  influenza  cases  and  309  cases  with  complications, 
found  that  his  mortality  was  about  22%.  Cases  treated  with  in- 
jections of  colloidal  tin  oxid  were  not  influenced  very  much.  He 
also  employed  normal  serum  and  collargol  without  much  effect.  A 
fixation  abscess  was  employed  in  some  cases  with  perhaps  better 
results.  Pehu  and  Pillon  claim  to  have  found  turpentine  injections 
useful  in  the  treatment  of  bronchopneumonia,  especially  in  children. 
Netter,  Vergely,  Roumaillac  and  also  Klingmuller  used  turpentine  in- 
jections. Swiss  clinicians  have  employed  the  fixation  abscess  with 
apparent  success.  Thus  Hodel  treated  156  cases  of  influenzal  pneu- 
monia. Of  these  102  were  treated  with  intravenous  injections  of  elec- 
targol,  the  dosage  being  from  5  to  20  c.c.  The  mortality  was  20%. 
In  15  cases  treated  with  the  fixation  abscess  the  results  were  much 
better.  Probst  describes  his  experience  in  the  epidemic  of  1920  as 
well  as  in  those  of  1918  and  1919.  His  experience  then  and  with 
recent  cases  has  confirmed  his  previous  announcements  in  regard  to 
the  benefit  from  a  fixation  abscess  induced  by  subcutaneous  injection 
of  1  c.c.  of  turpentine.  He  ascribes  its  efficacy  to  the  hyperleuko- 
cytosis  which  it  induces,  as  influenza  is  accompanied  by  pronounced 
leukopenia.  He  thinks  this  explains  also  why  influenza  is  mild  post- 
partum,  because  the  hyperleukocytosis  of  parturition  renders  the  in- 
fection mild,  and  there  is  nothing  so  effectual,  he  declares,  to  induce 
hyperleukocytosis  as  the  fixation  abscess.  He  warns  not  to  incise  the 


194  PROTEIN  THERAPY 

abscess  until  the  disease  is  subsiding  (apyrexia),  and  then  to  make  an 
ample  incision  and  clear  out  the  abscess  thoroughly. 

Niemeyer  has  used  intravenous  injections  of  gelatin,  but  only  in  a 
few  cases. 

Milk  has  been  used  by  a  number  of  clinicians.  Von  den  Velden 
treated  about  90  cases  with  serum,  as  well  as  milk,  with  results  which 
he  claims  were  very  satisfactory.  Of  the  milk  10  to  20  c.c.  were 
injected  intramuscularly  two  or  three  times  during  the  course  of  the 
disease.  Miinzer  and  Ptitz  also  found  that  milk  injections  favor- 
ably influenced  the  disease.  Patschkowski  treated  40  cases  of  in- 
fluenzal  pneumonia  with  milk  injections  (10  c.c.).  Repeated  injec- 
tions were  given  if  the  effect  was  not  sufficient  after  the  first  dose. 
In  this  series  8  patients  died.  He  observed  that  the  typical  reaction 
of  increased  fever  and  a  chill  were  often  lacking  when  the  injections 
were  made  in  such  pneumonic  patients.  Zalewski  and  Miiller  re- 
port very  favorable  results  after  the  injection  of  aolan,  a  milk  prepara- 
tion that  is  not  followed  by  a  severe  reaction. 

Serums. — Diphtheria  Antitoxin  was  repeatedly  given  a  trial. 
Kautsky  used  injections  of  about  3,000  units  and  claims  good  results. 
Vaubel  used  injections  of  1  c.c.  in  20  cases  with  favorable  results. 
Bettinger  treated  18  cases  with  satisfactory  results  and  Lustig  treated 
100  cases,  all  of  which  had  pulmonary  complications,  with  injections  of 
10  c.c.  of  antitoxin.  The  results  were  very  satisfactory  as  contrasted 
with  untreated  cases  in  the  same  clinic.  Crohn  also  reports  17  cases 
so  treated.  There  were  all  uncomplicated  influenza. 

Antistreptococcus  Serum  was  employed  by  Hughes  and  also  by 
Grote.  The  latter  treated  some  40  cases  with  antistreptococcus  serum, 
horse  serum  and  convalescent  serum  and  Maale  has  reported  similar 
results.  Friedemann  has  used  a  polyvalent  serum  in  20  cases  and 
considered  the  effect  favorable. 

Normal  Serum  and  Convalescent  Serum  have  found  extended  em- 
ployment, and  seemingly  with  satisfactory  clinical  results.  Reiss  used 
normal  serum,  convalescent  serum,  normal  horse  serum  and  diph- 
theria antitoxin,  injecting  from  20  to  200  c.c.  intravenously  with 
excellent  results.  The  temperature  usually  fell  within  36  to  48  hours. 
Grigant  and  Montier  made  use  of  the  plasma  serum  of  Richet — a  mixed 
rabbit  plasma  and  human  serum — which  when  injected  early  in  the 
course  of  the  disease  was  followed  by  satisfactory  results.  Other 
clinical  observations  have  been  reported  by  Pfeiffer  and  Prausnitz; 
Brodin,  Lesne  and  Saint-Girons,  Aguirre,  Ehrenberg  and  Bachmann, 
Huff-Hewitt;  Francis,  Hall  and  Gaines;  Hoist;  Ross  and  Hund, 
Luithlen  and  Winterberg,  Bogardus,  Pauly,  Redden,  Foldes  and 
Hajos,  O'Malley  and  Hartman,  Stoll,  Liebmann  and  others. 

Vaccines. — While  a  considerable  number  of  observers  have  used 
specific  vaccines  as  therapeutic  agents,  the  reaction  from  the  injec- 
tion of  influenza  bacilli  is  not  very  marked  and  the  nonspecific  effect 


INFECTIOUS  DISEASES  195 

therefore  not  pronounced.  Gow,  for  instance,  has  injected  75  million 
or  more  organisms  intravenously  without  producing  a  chill,  but  did 
observe  a  temperature  rise  of  2°  F.  after  three  hours.  There  is  little 
leukocytosis  to  be  observed  from  such  injections.  J.  Black  Milne 
has  reported  on  the  use  of  mixed  vaccines  and  Snyder  has  treated  20 
cases  with  intravenous  injections  of  typhoid  vaccine.  There  were 
no  deaths  in  the  series  and  Snyder  considered  the  method  of  decided 
value.  Cowie  and  Beaven  have  also  used  typhoid  vaccine  in  the 
treatment  of  pneumonia  but  consider  it  of  value  only  in  the  early 
stages  of  the  disease.  An  extensive  series  of  200  cases  has  been  re- 
ported by  Roberts  and  Gary  who  employed  a  vaccine  made  up  of  100 
million  organisms  per  cubic  cm.  of  each  of  the  following:  influenza 
bacilli,  pneumococci,  staphylococci  and  streptococci.  Of  this  vaccine 
they  injected  from  0.5  to  1  c.c.  intravenously.  In  their  series  so 
treated  there  was  no  evidence  of  injury  to  the  patients  in  any  way. 
The  mortality  of  the  treated  cases  was  9.5% ;  in  a  series  of  86  pa- 
tients not  treated  with  vaccine  the  mortality  was  31.2%.  In  the 
treated  series  36%  recovered  by  crisis,  in  the  untreated  series  20% 
so  recovered. 

Muck's  Vaccine. — Much,  Schmidt  and  Peemoller  have  reported 
on  the  use  of  a  nonspecific  vaccine  made  up  as  follows:  Reactive 
proteins  derived  from  a  number  of  nonpathogenic  bacteria;  a  lipoid 
mixture  from  bile  and  a  fat  mixture  of  animal  origin.  This  so-called 
"immunvollvaccine"  was  elaborated  on  the  basis  of  the  "partial  anti- 
gen" theory  of  Much's.  They  report  satisfactory  results  with  the 
vaccine  in  the  treatment  of  influenza. 

Hypertonic  Salt  Solution. — Borchardt  and  Ladwig  have  reported 
that  they  obtained  good  results  following  the  intravenous  injection 
of  small  amounts  of  salt  solution  (5-10%),  as  well  as  with  con- 
valescent serum.  Their  cases  numbered  98;  they  remark  particularly 
on  the  detoxication  evident  in  the  more  severe  cases. 

Albumoses. — Ten  severe  cases  of  influenza  were  treated  by  Liidke 
with  albumose  injections.  In  5  of  them  an  immediate  effect  of  a 
single  injection  was  apparent — the  patients  recovering  by  crisis.  In 
2  cases  pneumonia  developed  together  with  empyema.  Both  made 
protracted  recoveries.  In  3  cases  the  temperature  came  down  only 
after  a  number  of  injections. 


LETHARGIC  ENCEPHALITIS 

Laubie  and  Marinesco  report  the  rapid  recovery  of  patients  ill 
with  lethargic  encephalitis  following  intraspinal  injections  of  tetanus 
antitoxin.  Brill  has  also  used  spinal  injections  of  serum.  Grunwald 
has  injected  from  80  to  100  c.c.  of  convalescent  serum  intragluteally  in 
cases  of  lethargic  encephalitis.  The  effect  on  the  temperature  and 
pulse  rate  was  prompt,  lysis  occurring  in  3  days  after  the  injection. 


196  PROTEIN  THERAPY 

Neuralgias  persisted  for  some  time  after  the  temperature  had  returned 
to  normal.  Voorthius  claims  to  have  found  the  fixation  abscess  useful 
in  encephalitis. 

MEASLES 

Both  Holler  and  Miiller  have  treated  cases  with  albumose  and 
with  milk  injections.  Pehu  and  Pillon  report  that  injections  of  tur- 
pentine were  very  satisfactory. 

PAROTITIS  AND  ORCHITIS 

Salvaneschi  has  reported  that  the  injection  of  diphtheria  anti- 
toxin is  of  considerable  value  in  the  treatment  of  parotitis 
and  in  the  orchitis  frequently  complicating  parotitis.  More  re- 
cently Bonnamour  and  Bardin  have  reported  65  cases  of  mumps  which 
had  such  treatment  (20  c.c.  of  serum  subcutaneously).  Of  these  57 
entered  the  service  without  a  complicating  orchitis  and  none  of  them 
developed  this  complication;  in  8  there  was  testicular  pain  on  admis- 
sion with  a  beginning  orchitis  which  resolved  promptly  after  the  first 
or  second  injection.  They  consider  the  serum  injections  not  only 
of  value  in  the  treatment  of  the  orchitis,  but  as  a  prophylactic  against 
the  development  of  orchitis. 

PNEUMONIA  (LOBAR) 

In  the  chapter  on  the  Mechanism  of  the  Protein  Re- 
action the  effect  of  injections  on  the  course  of  lobar  pneumonia 
has  been  discussed.  As  we  might  expect,  severe  reactions  may 
be  followed  by  a  temporary  defervescence,  but  they  do  not  as  a  rule 
effect  the  pulmonary  lesion  when  once  it  is  established.  One  finds 
occasional  references  in  the  literature  in  which  foreign  protein  therapy 
has  been  used  with  a  measure  of  success  (Monguzzi — milk  and  gono- 
coccus  vaccine,  Talamon — diphtheria  antitoxin,  etc.),  but  the  method 
cannot  be  considered  of  established  value.  On  the  other  hand  it  is  by 
no  means  excluded  that  when  specific  serum  therapy  is  used  (chicken 
serum,  human  serum,  horse  serum),  or  specific  vaccine  therapy  (as 
for  instance  the  Rosenow  pneumococcus  autolysate)  part  of  the  thera- 
peutic effect  may  not  be  due  to  the  protein  injected.  Injections  such 
as  those  described  by  Huntoon  (soluble  antibodies)  always  bring 
about  a  marked  reaction  on  the  part  of  the  patient  and  are  effective 
only  when  given  early  in  the  course  of  the  disease,  observations  sug- 
gestive of  nonspecific  effects. 

PUERPERAL  INFECTIONS 

Lindig  tried  injections  of  casein  in  several  cases  of  puerperal  in- 
fection.   One  case  had  had  a  continuous  fever  for  two  months.    Three 


INFECTIOUS  DISEASES  197 

injections  of  1  c.c.  each  were  given  intravenously.  These  were  fol- 
lowed by  chills  which  usually  began  one  hour  after  the  injection; 
some  headache  was  also  noted.  After  the  first  injection  there  was  no 
temperature  rise,  nor  was  it  marked  after  the  second  injection  given 
the  following  day,  but  after  the  third  injection  was  made  4  days  later, 
there  was  a  reaction  of  2°  C.  The  patient  was  completely  cured 
after  the  third  injection.  Lindig  treated  several  other  cases  with 
similar  results. 

The  effect  here  noted  in  the  temperature  curve  was  reflected  in 
the  effect  on  the  leukocytes.  After  the  first  injection  there  was  usually 
only  a  slight  leukocytosis,  but  with  the  second  or  third  injection  this 
was  much  more  marked.  A  well-marked  euphoria  was  observed  in 
every  case. 

Kraus  in  his  early  work  on  heterovaccination  found  that  he  could 
bring  the  febrile  course  of  puerperal  infection  to  a  prompt  termi- 
nation by  injecting  typhoid  and  colon  vaccine  intravenously. 

Arweiler  in  a  Dissertation  has  taken  up  the  use  of  casein  injec- 
tions in  considerable  detail  and  Lindig  has  reported  on  the  use  of 
such  injections  as  a  method  of  prophylaxis  in  the  puerperium.  His  re- 
port covers  the  results  in  61  cases. 

The  colloidal  metals  have  been  used  with  some  success  (Siegel) ; 
Whitehouse  reports  success  following  the  intravenous  injection  of 
Flavine;  Werner  has  confirmed  the  earlier  reports  of  Kraus  in  using 
typhoid  vaccine.  Gow  uses  Witte  Peptone.  The  first  dose  which 
may  be  given  intravenously  to  a  septicemic  adult  is  from  8  to  10 
c.c.  The  quantity  is  increased  by  2  c.c.  every  other  day  or  so  until  16, 
18  or  20  c.c.  are  given  at  a  time.  The  injection  must  be  made  slowly 
and  for  that  reason  Gow  employs  Nolfs  technic  using  a  record 
syringe  and  a  very  fine  bore  needle — with  a  No.  28  it  is  impossible 
to  introduce  the  solution  too  quickly.  In  cases  of  puerperal  septicemia 
the  injection  of  peptone  tends  to  cause  an  immediate  and  rapid  fall 
in  blood  pressure,  a  rise  in  the  pulse  frequency,  and  if  the  patient 
has  a  leukocytosis,  it  rapidly  induces  a  high  degree  of  peripheral 
leukopenia — all  these  phenomena  being  of  very  short  duration.  Of 
these  changes,  the  easiest  to  record  as  a  guide  is  the  pulse  frequency, 
and  while  the  injection  is  in  progress  the  nurse  keeps  count  of  the 
radial  pulse,  calling  out  the  number  each  quarter  of  a  minute.  Though 
he  is  convinced  the  peptone  is  a  very  valuable  adjunct  to  sensitized 
vaccine,  Gow  makes  no  extravagant  claim  that  it  always  brings  a 
septicemia  to  an  end,  and  he  cautions  any  who  may  look  for  a  dramatic 
and  sustained  fall  of  temperature  after  its  use  that  most  times  they 
will  be  disappointed. 

Bianchi  gave  parenteral  injections  of  milk  in  thirty-six  obstetric 
and  twenty-one  gynecologic  cases.  He  reports  that  it  seemed  to  pro- 
mote and  accelerate  the  cure  in  certain  cases  and  ward  off  serious 
disturbances,  but  when  severe  puerperal  septicemia  was  under  way, 


198  PROTEIN  THERAPY 

no  benefit  could  be  detected.  Under  any  conditions  the  effect  did 
not  much  surpass  that  from  the  ordinary  measures,  drugs,  vaccines, 
fixation  abscess,  mercuric  chlorid  by  the  vein,  etc.  But  the  harmless- 
ness  of  this  milk  form  of  protein  therapy,  its  availability,  and  its  ex- 
cellent influence  in  reducing  objective  and  subjective  pain  and  in  en- 
hancing the  defensive  powers  of  the  organism,  impose  its  use  on  a  large 
scale,  he  declares,  especially  during  the  early  stage,  when  it  is  most 
potent. 

SCARLET  FEVER 

The  treatment  of  scarlet  fever  by  means  of  serum  injections  dates 
from  the  year  1897  when  both  v.  Leyden  and  Weisbecker  used  the 
serum  of  convalescent  patients  in  a  series  of  patients  ill  from  scarlet 
fever.  Jochmann  and  Rumpel  in  1903  tried  subcutaneous  injections, 
using  a  dose  of  about  20  c.c.,  without  obtaining  results  that  were  par- 
ticularly striking.  Indeed  the  results  from  subcutaneous  injection  have 
in  general  been  rather  unsatisfactory,  unless  huge  doses  are  used. 
It  was  not,  therefore,  until  Reiss  and  Jungmann  published  their  pa- 
per some  years  later  that  more  attention  was  given  the  subject. 
Since  that  time  Russian  and  Austrian  clinicians  have  reported  ex- 
tensively on  the  use  of  antistreptococcus  serum,  with  at  times  excel- 
lent results.  Apart  from  convalescent  serum,  the  antistreptococcus 
serum  of  Moser,  prepared  by  immunizing  horses  with  strains  of 
streptococci  freshly  isolated  from  fatal  cases  of  scarlet  fever,  has 
met  with  considerable  success  (Axenow). 

In  the  earlier  period  the  serum  was  given  subcutaneously  and 
the  results  were  never  striking.  Reiss  and  Jungmann,  however,  used 
their  serum  intravenously  and  with  this  method  of  injection  the  re- 
sults have  been  much  more  satisfactory.  Convalescent  serum  being 
rather  difficult  to  obtain  in  large  quantity  the  injections  have  been 
limited  as  a  rule  to  about  20-90  c.c.,  while  with  other  serums  the  dosage 
has  been  much  larger,  several  hundred  c.c.  being  used.  Jochmann, 
who  followed  this  form  of  therapy  for  a  number  of  years,  considers 
that  intravenous  serum  injections,  if  given  early  in  toxic  cases,  lessen 
the  toxicity,  usually  hasten  defervescence  and  seem  to  lessen  the 
number  and  severity  of  postscarlatinal  complications. 

Synnott  has  also  reported  on  the  use  of  convalescent  serum  and 
Weaver  has  discussed  the  question  fully. 

Glaser  has  recently  reported  a  series  of  grave  scarlet  fever  cases 
treated  with  pooled  convalescent  serum.  In  15  cases  it  was  given  intra- 
muscularly in  doses  of  from  50-80  c.c.  In  40%  of  these  cases  the 
temperature  came  down  by  prompt  lysis.  Complications  did  not  seem 
to  be  influenced  by  the  treatment.  In  28  cases  in  which  the  serum 
was  administered  intravenously  the  effect  on  the  temperature  curve 
was  apparent  in  every  case.  Occasionally  the  intravenous  injection 
was  followed  by  a  chill,  some  headache  and  temporary  weakness,  but 


INFECTIOUS  DISEASES  199 

he  saw  no  unfavorable  result  from  the  injections.  All  recent  ob- 
servers insist  that  if  effects  from  the  serum  are  to  be  expected  the 
same  must  be  given  within  the  first  three  days  of  the  illness.  (Rowe, 
Bennecke,  Zingher,  Koch,  Moog,  Reiss  and  Hertz,  etc.) 

Moog  as  well  as  several  other  clinicians  used  normal  serum  in  doses 
of  80-100  c.c.  In  25  cases  7  responded  with  a  critical  drop  in  the 
temperature;  13  dropped  by  lysis;  2  cases  died,  while  in  3  there 
was  no  effect. 

Rehde,  who  treated  89  cases,  used  normal  serum  in  14.  In  both 
series  the  results  were  equally  satisfactory.  Usually  a  mild,  general 
reaction  was  observed  following  the  intravenous  injection,  that  is, 
the  temperature  was  increased  for  a  short  time,  a  chill  noted,  as 
well  as  some  headache.  Griesbach  in  a  series  of  21  cases  observed 
this  reaction  repeatedly  in  his  series  (8  out  of  21  reacted  with  a 
chill)  and  4  patients  went  into  collapse.  Krause,  who  treated  28  cases 
of  scarlet  fever  with  convalescent  serum,  also  has  observed  collapse 
symptoms  in  a  large  percentage  of  the  cases  (25%).  In  his  series 
there  were,  however,  only  4  deaths  and  in  24  the  temperature  came 
down  promptly  after  the  injections. 

This  collapse  observed  by  Griesbach  and  Krause  is,  however,  quite 
unusual  and  Reiss,  who  has  so  far  treated  221  cases,  states  that  he 
has  never  had  one  case  in  which  collapse  and  death  followed  the  in- 
jection. Schultz  and  Ehrmann  have  also  treated  a  large  number 
of  cases  with  intravenous  serum  injections.  Ehrmann's  cases  numbered 
over  200  and  his  results  were  very  favorable.  He  emphasized  the  im- 
portance of  injecting  early  in  the  course  of  the  disease  if  results  are 
to  be  expected. 

Schultz'  cases  numbered  184,  of  whom  102  were  treated  with 
normal  serum,  67  with  convalescent  and  15  with  both  kinds  of  serum. 
He  reports  very  apparent  improvement  in  about  60%  of  the  cases 
following  the  injections. 

Prinzing  has  studied  the  effect  of  serum  treatment  on  the  com- 
plications with  the  following  results:  Lymphadenitis  collci  occurred 
in  15.5%  of  the  injected  cases,  in  34%  of  the  noninjected;  otitis  media 
in  9.3%  of  the  injected,  in  10.8%  of  the  noninjected;  nephritis  in 
8.2%  of  the  treated  and  in  18.9%  of  the  nontreated  cases. 

Holler  has  published  a  series  of  32  cases  of  scarlet  fever  treated 
with  injections  of  deutero-albumose  (twice  daily,  1  c.c.  of  a  10% 
solution).  There  were  no  deaths  in  the  series  and  no  complications. 
The  course  of  the  disease  was  in  each  instance  shortened. 

Liidke  treated  14  cases  of  severe  scarlet  fever  with  albumose  in- 
jections. The  fever  very  frequently  ceased  promptly  after  a  single 
injection,  the  skin  eruption  likewise  fading  and  the  exfoliation  began 
very  promptly.  There  were  no  complications  and  no  nephritis  was 
observed.  There  was  no  doubt  in  Liidke's  opinion  that  the  injec- 
tions resulted  in  a  material  shortening  of  the  course  of  the  disease. 


200  PROTEIN  THERAPY 

In  general  it  may  be  stated  that  following  the  intravenous  in- 
jection of  convalescent  human  serum,  normal  human,  as  well  as 
horse  or  other  serum  in  cases  of  grave  scarlet  fever,  the  patient  re- 
acts with  a  slight  increase  in  temperature  and  occasionally  with  a 
chill;  in  the  majority  of  cases  this  is  followed  by  a  prompt  lysis  or 
crisis.  The  toxic  manifestations  of  the  infection  are  usually  dimin- 
ished, the  patient  feels  better,  complications  are  diminished  in  num- 
ber, but  preexisting  complications  are  not  influenced  appreciably. 

There  seems  very  little  that  is  specific  in  the  reaction,  for  it  is  im- 
material whether  immune  streptococcus  serum,  convalescent  serum, 
normal  human  or  animal  serum  is  used,  or  whether  proteoses  (al- 
bumoses)  are  employed.  Even  salvarsan,  according  to  Jochmann,  is 
followed  by  a  typical  reaction  on  the  part  of  the  patient,  in  effect 
similar  to  serum  injection,  so  that  he  considers  the  employment  of 
the  one  or  the  other  merely  a  matter  of  individual  preference. 


SEPTICEMIA 

The  treatment  of  septicemia  by  means  of  nonspecific  injections 
has  at  times  undoubtedly  yielded  brilliant  clinical  results;  more  often, 
unfortunately,  there  has  been  no  apparent  effect  on  the  course  of 
the  disease.  Perhaps  the  failures  are  due  to  the  fact  that  nonspe- 
cific therapy  has  almost  invariably  been  left  as  a  final  resort  when 
the  patient  was  quite  exhausted  and  incapable  of  stimulation.  It  is 
to  be  remembered  that  the  very  fact  that  in  the  true  septicemia 
we  are  dealing  with  bacterial  proliferation  in  the  blood  stream  and 
that  thereby  all  parts  of  the  organism  are  already  being  stimulated 
— or  overstimulated  as  the  case  may  be — makes  any  therapeutic  ap- 
plication of  this  nature  practically  hopeless  at  the  very  start.  Never- 
theless one  does  at  times  witness  quite  remarkable  and  dramatic  re- 
coveries by  crisis  or  by  lysis  after  nonspecific  injections.  The  older 
literature,  in  which  the  injection  of  colloidal  metals  was  dealt  with, 
is  quite  extensive  and  need  not  be  reviewed  at  this  time.  The  re- 
sults were  on  the  whole  inconclusive.  While  recoveries  were  observed 
that  seemed  definitely  contingent  on  the  therapeutic  injection;  in  other 
cases  there  was  no  apparent  result.  Reichmann  (6  cases,  5  deaths). 

In  the  more  recent  literature  other  procedures  have  been  mentioned, 
some  of  which  seem  to  have  been  followed  by  very  favorable  and  con- 
sistent results.  Brown  has  discussed  the  use  of  the  metallic  colloidal 
preparations.  Hypertonic  sugar  has  found  advocates  (Baradulin, 
Audain  and  Masmonteil),  and  immunized  blood  has  also  been  used 
(Steel).  Wright  has  suggested  a  method  of  using  such  immunized 
blood  for  transfusion.  The  mode  of  preparation  is  to  treat  the  blood 
of  a  healthy  individual  with  vaccine,  then  transfuse  the  infected  in- 
dividual with  such  immunized  blood. 


INFECTIOUS  DISEASES  201 

Kalberlah  claims  to  have  obtained  very  good  results  by  injecting 
typhoid  vaccine. 

Gow  has  recently  used  peptone  injections  for  intravenous  injections 
in  septicemias  and  has  combined  them  with  subcutaneous  injections  of 
streptococcus  vaccine  (sensitized).  By  this  method  he  claims  to  have 
obtained  excellent  results;  Nolf,  too,  has  had  success  with  peptone 
injections. 

In  two  cases  of  streptococcus  sepsis  recovery  occurred  in  4  and  8 
days  respectively  after  intravenous  injection  of  deutero-albumose. 
(Liidke.)  There  was  a  very  severe  chill  after  the  injections.  In  one 
case  of  tetragenous  sepsis  there  was  prompt  recovery  after  a  single 
injection. 

Among  the  more  recently  introduced  colloidal  metal  preparations 
"argochrom,"  a  methylene-blue-silver  combination,  seems  to  have 
found  considerable  favor.  Wendt  treated  14  cases  with  this  agent  and 
considers  it  of  value. 

Weichardt  in  a  recent  paper  which  takes  up  the  effect  of  protein 
therapy  in  the  pneumonococcus  sepsis  of  mice,  states  that  both  Jaschke 
and  Freund  have  obtained  favorable  results  in  septic  cases  with  protein 
therapy. 

SMALLPOX 

Holler  reports  on  the  treatment  of  variola  with  daily  intravenous 
injections  of  deutero-albumose.  The  results  are  described  as  satisfac- 
tory. 

TETANUS 

A  rather  remarkable  experience  is  that  reported  by  Liidke  in  the 
treatment  of  7  cases  of  tetanus.  These  were  all  cases  in  which  severe 
spasm  had  developed  after  incubation  periods  of  from  7  to  11  days. 
The  treatment  consisted  of  injections  of  deutero-albumose  of  from  3 
to  5  c.c.  of  a  10%  solution,  given  in  24-  or  48-hour  intervals.  No  spe- 
cific serum  and  no  magnesium  sulphate  was  used.  All  cases  recovered 
in  from  7  to  22  days.  Liidke  observed  the  characteristic  effect  of  non- 
specific therapy  on  nerve  irritability  in  that  the  spasms  were  first  aug- 
mented after  the  injections,  then  diminished  in  intensity.  Kaznelson 
also  treated  two  cases  with  albumose  injections.  One  case  recovered, 
the  other  ended  fatally. 

TRENCH  FEVER 

Paul  Jungmann  treated  a  large  series  of  cases  of  trench  fever 
(Wolhynian  Fever)  with  colloidal  metals  without  result,  despite  the 
fact  that  a  typical  nonspecific  reaction  was  elicited,  with  a  severe 
chill,  fever,  etc.  Often  the  patient  was  seemingly  cured,  with  the 
temperature  curve  normal  and  the  other  symptoms  in  abeyance,  but 
finally  the  clinical  course  of  the  disease  again  became  manifest. 


202  PROTEIN  THERAPY 

With  typhoid  vaccine  and  old  tuberculin  a  similar  reaction  and  ef- 
fect was  obtained,  just  as  one  finds  that  as  a  result  of  intercurrent 
infections,  pneumonia,  etc.,  the  symptomatology  of  the  trench  fever 
may  almost  completely  disappear.  The  nonspecific  injections,  accord- 
ing to  Jungmann,  had  no  direct  effect  on  the  course  of  the  disease 
other  than  described. 

Kirchberg,  on  the  other  hand,  who  used  collargol  intravenously, 
states  that  during  the  time  that  the  patients  were  under  observation 
there  was  no  return  of  the  fever  after  the  injections,  and  the  anemia 
was  also  markedly  improved.  Richter,  too,  found  that  collargol  in- 
jections were  followed  by  satisfactory  results. 

TUBERCULOSIS 

In  the  discussion  of  the  focal  reaction  and  the  relation  of  the 
skin  reactions  to  nonspecific  factors,  evidence  has  been  presented  that 
tuberculins  are  active  as  non-specific  agents  and  it  should  be  kept 
in  mind  that  their  therapeutic  effect  can  be  accounted  for  largely 
on  such  a  basis.  In  a  general  way  the  experience  with  tuberculins 
has  been  the  following:  Large  doses  in  active  cases  cause  a 
rapid  progression  of  the  disease,  with  cavity  formation,  increased 
tendency  to  hemorrhage,  etc.  Even  small  doses  in  active  cases  are 
not  without  some  danger.  In  the  inactive  cases  large  doses  may  acti- 
vate the  focus ;  moderate  doses  may  be  followed  by  an  improvement,  or 
no  apparent  effect  on  the  focus.  In  incipient  cases  large  doses  may 
occasionally  be  followed  by  complete  and  rapid  recovery;  more  often 
though  the  effect  is  a  harmful  one. 

Keeping  in  mind  the  fact  that  resistance  to  tuberculosis  is  largely 
cellular  and  that  the  effect  of  nonspecific  stimulation  is  always  at 
first  associated  with  increased  digestive  phenomena,  we  might  antici- 
pate these  effects.  An  active  process  will  be  made  more  active,  an 
inactive  one  may  be  activated;  on  the  other  hand,  a  small  incipient 
lesion  may,  by  activation,  digestion,  etc.,  occasionally  be  rapidly 
healed. 

In  a  general  way  this  agrees  with  the  experience  that  has  been 
gained  with  protein  therapy  in  the  treatment  of  pulmonary  tuberculosis. 

Holler  found  that  while  early  cases  may  react  well  and  there  may 
be  an  increase  in  the  general  resistance,  advanced  cases  may  give 
noticeable  evidence  of  autolysis  and  extended  cavity  formation. 
Mueller  found  that  if  he  treated  cases  with  slight  apical  lesions 
and  only  moderate  evidence  of  activity,  the  entire  process  might  be 
cleared  up  after  a  few  injections  of  milk.  Naturally  in  such  cases 
we  bring  about  a  decided  focal  reaction  and  the  organism  must  be  in 
physical  condition  to  withstand  and  detoxicate  all  the  necrotic  ma- 
terial that  is  liberated  by  the  digestion  at  the  point  of  infection  and 
to  destroy  bacilli  that  are  freed  in  the  process.  If  it  cannot  do  this 
we  will  merely  spread  the  infection. 


INFECTIOUS  DISEASES  203 

Schmidt  and  Kraus  report  very  remarkable  results  following  milk 
injections  in  early  tuberculosis;  Klemperer  has  gone  over  a  somewhat 
larger  series  of  cases  but  could  not  confirm  their  findings. 

Czerny  and  Eliasberger  have  attacked  the  problem  from  another 
point  of  view.  They  have  taken  a  series  of  very  emaciated  tuber- 
culous children  (26)  and  have  given  them  frequent  injections  (daily 
injections  of  from  %  to  1  c.c.)  of  horse  serum.  While  the  injections 
have  no  direct  effect  on  the  tuberculous  process,  12  of  the  children 
showed  a  striking  improvement  in  general  condition.  This  effect  on 
the  nutrition  and  on  the  general  condition  of  children  has  been  re- 
ported by  other  observers  as  well. 

Tuberculous  Meningitis. — Hollis  and  Pardee  call  attention  to  the 
use  of  intraspinal  injections  of  foreign  protein  (they  used  antimen- 
ingitis  serum)  in  the  treatment  of  tuberculous  meningitis,  reporting 
the  recovery  of  5  patients  out  of  a  series  of  8.  They  regard  the  therapy 
as  nonspecific,  and  call  attention  to  the  fact  that  the  use  of  serum  in 
the  treatment  of  syphilis  of  the  spinal  cord — although  combined  with 
a  specific  drug — must  also  be  regarded  as  a  form  of  therapy  based 
on  the  irritation  of  the  meninges,  with  the  therapeutic  effect  following 
as  a  result  of  the  reaction. 

Experimentally  Baldwin  and  L'Esperance  have  noticed  some  in- 
crease in  fibrosis  in  tuberculous  guinea  pigs  after  treatment  with 
typhoid  vaccine.  Bohme,  using  a  variety  of  nonspecific  substances, 
vaccinurin,  pus,  influenza  bacilli,  streptococci  and  milk  injections, 
could  determine  no  alteration  in  the  course  of  tuberculosis  in  the 
guinea  pig. 

TYPHUS  FEVER 

During  the  course  of  the  war  a  number  of  investigators  have  had 
the  opportunity  of  trying  nonspecific  therapeutic  agents  in  typhus 
fever.  These  have  included  deutero-albumose,  salt  solution,  colloidal 
metals,  convalescent  serum  and  vaccines  of  various  kinds. 

Holler  found  that  his  method  of  therapy — daily  injections  of 
deutero-albumose  intravenously — was  most  efficacious  in  typhus  when 
he  was  able  to  begin  the  treatment  within  the  first  two  days  after 
the  onset;  in  that  case  he  was  frequently  able  to  terminate  the  disease 
by  crisis.  When  given  later,  while  it  shortened  the  course  of  the 
disease  and  had  a  pronounced  effect  in  modifying  toxicity,  the  re- 
sults were  not  so  striking. 

In  fifteen  untreated  cases  the  mortality  was  about  50%.  In  50 
treated  cases  only  three  patients  died. 

Equally  favorable  results  have  been  described  by  Tagle,  who 
began  such  therapy  on  the  basis  of  Nolfs  work,  and  by  Opazo. 
Tagle  applied  the  injections  in  59  cases  of  typhus.  Aside  from  one 
patient  that  died  in  less  than  forty-eight  hours,  the  mortality  was 
about  5  per  cent.  He  declares  that  the  absence  of  all  ill  effects 


204  PROTEIN  THERAPY 

confirms  the  harmlessness  of  the  method  for  all  ages.  The  general 
health  improves,  the  duration  of  the  disease  is  shortened,  and  con- 
valescence sets  in  earlier.  The  benefit  was  more  pronounced  the 
earlier  the  injections  had  been  begun.  His  report  represents  exten- 
sive research  by  the  different  physicians  on  the  hospital  staff,  much 
experimental  and  laboratory  work  being  carried  on  preliminary  to  and 
during  the  clinical  experiences.  Nolf's  technic  was  closely  followed, 
except  that  the  acidity  of  the  solution  of  peptone  in  physiologic  salt 
solution  was  reduced  to  4.3  per  thousand,  and  the  remedy  was  put 
up  in  5  c.c.  capsules.  About  10  c.c.  was  given  as  the  first  dose,  to 
robust  adults;  otherwise  from  4  or  5  c.c.  For  older  children,  up  to 
6  or  8  c.c.  giving  afterward  only  about  half  of  the  initial  dose,  and 
allowing  an  interval  of  forty-eight  hours  to  elapse.  In  almost  all  the 
cases  a  second  injection  was  given  and,  exceptionally,  a  third,  with 
only  1  or  2  c.c.  A  subcutaneous  injection  of  2  or  3  c.c.  of  20  or  25 
per  cent,  camphorated  oil  was  given  every  six  hours  day  and  night, 
with  0.25  c.c.  of  1  per  thousand  epinephrin  in  each  syringe.  The 
patient  must  be  kept  in  repose.  The  blood  pressure  falls  during  and 
immediately  after  the  intravenous  injection  of  peptone,  but  if  it  is 
made  slowly  (1  c.c.  per  minute)  and  if  epinephrin  has  been  given, 
the  drop  is  slight.  The  coagulation  time  of  the  blood  is  much  re- 
tarded. Analysis  of  the  blood  showed  that  the  urea  content  could  be 
disregarded  with  this  protein  therapy  as  the  latter  only  slightly  aug- 
mented it,  and  it  soon  dropped  to  below  its  previous  figure  from  the 
rapid  reaction  to  the  injection,  while  the  dietetic  restrictions  in 
typhus  aid  in  its  being  speedily  cast  off.  Analysis  of  the  urine  like- 
wise showed  that  the  injections  of  peptone  had  no  detrimental  in- 
fluence on  the  kidneys  and  hence  there  were  no  centra-indications 
on  the  part  of  the  kidneys,  except,  of  course,  with  grave  nephritis. 
There  are  no  characteristic  findings  in  the  urine  in  typhus.  The 
fever  charts  given  show  the  attenuating  and  abbreviating  influence 
of  the  protein  therapy  better  than  anything  else.  An  interesting  fea- 
ture of  the  cases  was  that  when  the  temperature  had  gone  down  un- 
der the  injections,  a  further  injection  did  not  induce  any  appreciable 
reaction.  The  production  of  antitoxins  can  then  be  regarded  as  suffi- 
cient and  the  case  as  cured.  In  every  case  improvement  in  the  general 
condition  was  unmistakable. 

Opazo  reports  the  application  of  Nolf's  method  in  27  cases  of 
typhus,  with  14  recoveries,  4  in  convalescence  and  7  still  under  treat- 
ment ;  2  of  the  patients  died,  but  the  disease  in  their  cases  had  reached 
a  stage  when  reaction  was  no  longer  possible.  He  reiterates  that  the 
protein  therapy  induced  a  favorable  reaction  which  modified  the 
disease  and  all  the  symptoms.  In  his  experience  the  reaction  was 
prompter  and  more  effectual  in  children  than  in  adults.  He  is  now 
applying  this  protein  therapy  as  the  routine  in  all  cases  of  typhus. 

Kalberlah  reports  good  results  from  the  intravenous  injection  of 


INFECTIOUS  DISEASES  205 

typhoid  vaccine.  Bouygues  has  employed  colloidal  metals  and 
Coglievina,  who  used  dispargin — a  colloidal  silver  preparation, — re- 
ports that  the  course  of  the  disease  was  much  less  toxic  and  the  mor- 
tality lower  than  in  untreated  cases.  He  gave  on  an  average  about 
4  injections.  Tietze  used  a  3%  solution  of  collargol  (5  c.c.)  and 
noted  a  lessening  of  the  toxicity. 

The  use  of  silver  and  antimony  colloids  has  been  suggested  by 
Uhlenhuth  and  Frommes,  but  the  number  of  cases  treated  by  them  has 
been  too  small  to  justify  final  conclusions. 

Gyozi  treated  a  number  of  cases  with  autoserotherapy  and  found 
that  it  seemed  of  decided  benefit  particularly  in  the  older  cases. 
Gudzent  treated  two  cases  with  convalescent  serum  without  apparent 
success.  Raubitschek  treated  25  cases  with  subcutaneous  injections  of 
normal  horse  serum.  The  mortality  was  about  6%.  v.  Zielinski 
used  intravenous  injections  of  the  patient's  own  cerebrospinal  fluid.  In 
20  severe  cases  5  died.  Munk  has  published  a  comparative  study 
of  the  treatment  of  typhus  with  normal  horse  serum,  peptone  and 
with  nucleohexyl.  More  recently  Schultz,  Charlton  and  Hatziewas- 
silow  have  discussed  a  heterovaccine  iriethod  which  they  claim  has 
given  good  results.  They  used  2  loops  of  48  hours'  growth  of  typhoid 
organisms  (killed  at  60°  C.)  which  were  mixed  with  5  c.c.  of  the  pa- 
tients' serum.  This  sensitized  vaccine  was  then  injected.  A  rather 
sharp  reaction  followed  the  injection  but  the  clinical  results  seemed 
very  satisfactory.  In  the  series  of  5  cases  all  recovered. 

Perhaps  a  method  that  is  equally  successful  is  that  described  by 
Danielopolu  in  his  recent  treatise  on  Typhus  Fever.  The  author  uses 
daily  injections  of  hypotonic  salt  solution  (0.065)  which  are  given 
intravenously.  In  his  untreated  series  the  mortality  was  very  great, 
in  the  treated  fully  90%  recovered. 

VINCENT'S  ANGINA 

Capitan  treated  200  cases  of  Vincent's  angina  with  intramuscular 
injections  of  colloidal  arsenic  (6  c.c.).  The  cure  was  complete  in 
from  24  to  48  hours.  No  local  treatment  was  necessary.  Stuhl  re- 
ports a  similar  nonspecific  method  of  therapy  in  using  tuberculin 
in  the  treatment  of  Vincent's  angina.  While  he  treated  but  a  small 
number  of  cases  the  results  were  quite  striking. 


CHAPTER  XII 
SPIROCHETAL  AND  PROTOZOAL  INFECTIONS 

RELAPSING  FEVER 

Bouygues  reports  that  he  has  found  the  injection  of  colloidal 
metals  useful  in  relapsing  fever. 

SYPHILIS 

The  fact  that  intercurrent  diseases,  particularly  the  acute  infectious 
diseases,  have  a  distinct  effect  on  the  manifestations  of  syphilis  has 
been  frequently  observed  by  clinicians  (Zehner).  The  effect  may 
be  apparent  in  delaying  the  onset  of  secondary  eruptions  or  in  hasten- 
ing the  involution  of  skin  lesions  already  present.  Neumann  has  dis- 
cussed the  subject  quite  thoroughly  in  Nothnagel's  Special  Pathology. 

In  view  of  the  effect  of  temperature  it  was  natural  that  with  the 
study  of  protein  therapy  efforts  would  be  made  to  determine  what 
effects  would  be  apparent  on  syphilitic  skin  lesions  after  nonspecific 
injections,  and  Biach  as  well  as  Kyrle,  Weiss  and  Luithlen  have  de- 
scribed the  involution  of  the  skin  lesions  after  protein  therapy.  Nat- 
urally the  question  is  of  greater  theoretic  than  practical  interest  be- 
cause we  are  fortunate  in  possessing  much  more  efficient  specific 
agents. 

In  the  last  two  years  considerable  attention  has  been  devoted 
to  the  study  of  silver  preparations  and  their  application  in  syphilis. 
The  injection  of  colloidal  silver  has  been  found  experimentally  to 
prevent  the  proliferation  of  spirochetes  in  the  tissues  of  rabbits 
(Kolle  and  Ritz)  and  silver  preparations  (collargol)  have  been  used 
(see  v.  Notthafft)  clinically  with  apparent  success.  Silver-salvarsan 
is  not  included  in  this  category  because  its  effect  is  of  course  es- 
sentially specific. 

The  effect  of  iodids  should  undoubtedly  be  included  in  the  group 
of  nonspecific  agents  because  the  mode  of  action  in  stimulating  tissue 
autolysis  (although  by  an  indirect  method,  as  demonstrated  by  Jobling 
and  Petersen)  is  quite  analogous.  It  is  very  probable  that  the  non- 
specific agents  will  have  a  place  in  the  treatment  of  syphilis  as  ad- 
juvants that  permit  us  to  make  specific  treatment  more  intense  by 
facilitating  the  rapid  distribution  of  the  specific  agent.  Applications 
have  been  made  of  this  theory  by  Schacherl,  by  Hauber  and  by 
Szedlack. 

206 


SPIROCHETAL  AND  PROTOZOAL  INFECTIONS       207 

Schacherl  has  reported  on  the  combined  specific  and  nonspecific 
treatment  of  10  syphilitic  neuro-arthr apathies.  In  these  cases  only  one 
was  temporarily  cured,  5  showed  some  retrograde  change,  while  4 
were  unchanged. 

In  16  cases  of  cerebral  lues,  the  results  were  as  follows:  In  5 
cases  of  hemoplegia,  1  was  cured,  3  were  improved.  Five  were  of  the 
disseminate  type;  of  these  2  were  cured,  3  improved.  Three  cases 
presented  only  eye  symptoms.  One  of  these  was  cured,  one  improved 
and  one  not  changed. 

Schacherl  noticed  that  the  Wassermann  reaction  was  much  more 
rapidly  changed  under  the  combined  treatment  than  with  mercurial 
treatment  alone;  it  seemed  very  probable  that  the  mercury  was  much 
more  rapidly  absorbed,  because  stomatitis  was  more  frequently  noted 
under  the  combined  method  than  when  mercury  salicylate  was  given 
alone. 

Stiickgold,  who  has  treated  a  number  of  cases  of  congenital  lues 
with  the  milk  "fever"  therapy,  rightly  observes  that  one  cannot  expect 
to  permanently  cure  syphilis  by  means  of  such  therapy;  all  that  one 
can  expect  is  a  remission  of  the  disease  manifestation.  But  he  is 
convinced  that  the  combination  of  the  nonspecific  reaction  with  spe- 
cific agents  is  of  particular  value.  He  observed  that  with  the  combined 
therapy  one  required  much  smaller  doses  of  the  specific  drugs  to 
obtain  therapeutic  results  and  to  influence  the  Wassermann  reaction. 

Schreiner  used  milk  and  peptone  injections  along  with  specific 
treatment  in  syphilis  and  found  that  the  Wassermann  reaction  be- 
came negative  much  sooner  in  such  cases  than  in  those  that  were 
put  solely  on  specific  treatment.  The  effect  on  the  Wassermann  re- 
action has  been  studied  by  several  observers  after  Uddgren  called 
attention  to  the  fact  that  in  luetics  a  single  injection  of  milk  might 
render  the  serum  positive  (previously  negative).  Scherber  found  that 
in  luetics  an  intercurrent  febrile  disease  might  have  the  same  effect. 
In  the  therapy  of  syphilis  by  means  of  salvarsan  the  induction  of  an 
antianaphylactic  state  on  the  part  of  the  patient  has  been  found  of 
value  in  preventing  the  occurrence  of  the  salvarsan  shock  reaction. 
Bushman  describes  the  method  of  Stokes,  which  consists  of  giving  a 
preliminary  dose  of  salvarsan  (1/10  the  total  dose) ;  this  is  undoubt- 
edly sufficient  to  cause  an  alteration  in  the  permeability  of  the  cells 
and  so  lessen  the  possibility  of  later  intoxication.  Mention  has  already 
been  made  of  the  fact  that  Jungmann  used  salvarsan  interchangeably 
with  serum  in  the  treatment  of  scarlet  fever. 

WEIL'S  DISEASE 

A  number  of  observers  have  reported  that  Weil's  disease  is  fa- 
vorably influenced  by  the  injection  of  convalescent  and  normal  serum 
(Heidenheim,  Herbach,  Mann;  Kleinberger  obtained  no  conclu- 


208  PROTEIN  THERAPY 

sive  results).  Inasmuch  as  milk  injections  seem  to  be  very  active 
in  influencing  the  liver  (increase  in  thrombokinase,  fibrinogen,  shed- 
ding of  glycogen,  etc.)  Dollken  determined  to  use  milk  therapy  in 
place  of  the  serum — either  normal  or  convalescent.  The  styptic  ef- 
fect of  the  milk  injections  might  be  expected  to  become  manifest  in 
the  course  of  the  disease.  In  one  very  severe  and  quite  hopeless  case 
he  injected  3  c.c.  of  milk;  the  bleeding  from  the  intestine  ceased  after 
five  hours  but  the  patient  nevertheless  died.  In  other  less  toxic  cases 
Dollken  observed  a  decided  effect  on  the  pigmentation  of  the  skin. 
In  several  cases  injected  with  albumoses  and  with  milk  there  was 
practically  a  clearing  of  the  jaundice  in  from  48  to  72  hours.  A  mild 
grade  of  jaundice  persisted,  however,  in  these  cases  despite  further 
injections.  The  effect  on  the  albuminuria  was  also  quite  marked,  a 
single  injection  being  sufficient  to  completely  clear  up  the  urinary 
findings.  Dollken  was  not  able  to  follow  his  cases  for  any  length  of 
time  so  that  it  is  not  possible  to  draw  any  positive  conclusions  from 
the  work.  There  seems  little  doubt  that  nonspecific  injections,  par- 
ticularly of  milk,  are  able  to  effect  the  liver  metabolism  considerably 
and  may  so  alter  disease  processes  which  have  their  principal  effect 
in  the  liver  parenchyma.  Inada  and  his  associates  have  also  studied 
the  effect,  of  the  injection  of  serum  on  the  course  of  Weil's  disease. 


MALARIA 

Activation. — The  provocative  effect  of  'nonspecific  injections  has 
been  made  use  of  not  only  in  activating  latent  gonococci,  but  also  in 
cases  of  suspected  malaria. 

Thaller  noticed  that  after  milk  injections  in  cases  that  were  sus- 
pected of  malarial  infection  the  plasmodia  could  be  demonstrated  after 
the  reaction  in  a  certain  number  of  cases.  In  thirty  cases  so  in- 
jected 13  responded  with  the  usual  milk  fever,  in  12  a  malarial  type 
of  fever  was  activated,  in  5  there  was  no  effect.  Habetin  used  sub- 
cutaneous injections  of  nucleic  acid  to  mobilize  the  plasmodia  and 
Heese  found  that  after  nonspecific  injections  plasmodia  could  be  dem- 
onstrated and  paroxysms  commenced  one  week  after  the  injection. 
Schlesinger  observed  that  malaria  plasmodia  were  mobilized  after 
typhoid  inoculation;  Freund  also  observed  the  activation  of  an  old 
malaria  after  an  intravenous  typhoid  injection,  while  Zupnik, 
v.  Miiller  and  Leiner  report  an  interesting  case  of  a  double  infection 
with  typhoid  and  malaria  in  which  the  malarial  paroxysms  resulted 
in  a  typical  nonspecific  defervescence  of  the  typhoid  fever. 

Therapy. —  Silvestri  would  support  the  specific  treatment  of 
malaria  with  injections  of  foreign  protein,  serum,  adrenalin,  strychnin, 
etc.,  claiming  that  the  combined  treatment  is  better  than  when  quinin 
is  used  alone.  It  is  very  possible  that  such  measures  may  be  useful 


SPIROCHETAL  AND  PROTOZOAL  INFECTIONS       209 

in  facilitating  the  diffusion  of  the  specific  drug  and  getting  more  effect 
on  latent  foci  of  the  plasmodia. 

Schimert  reports  the  treatment  of  some  70  cases  of  tropical  ma- 
laria which  had  become  refractory  to  quinin.  These  were  chronic 
cases  and  in  poor  physical  condition.  He  tried  autoserotherapy  and 
obtained  a  clinical  recovery  in  85%  of  the  cases,  that  is,  the  patients 
were  improved  physically,  gained  in  weight  and  were  able  to  be  at 
work,  although  the  parasites  were  not  altered  by  the  treatment  in- 
stituted. 


CHAPTER  XIII 

MISCELLANEOUS   DISEASES 

ASTHMA 

The  recognition  that  asthma  and  hay  fever  were  to  be  grouped 
among  diseases  due  to  sensitization  of  the  patient  in  the  nature  of  an 
anaphylaxis,  has  opened  a  series  of  exceedingly  valuable  and  interest- 
ing investigative  and  clinical  problems.  Naturally  the  asthmas 
due  to  cardiac  impairment  or  anatomical  alterations  result- 
ing from  tuberculosis  cannot  be  included  in  such  a  category, 
but  there  is  evidence  accumulating  that  in  this  latter  group  of 
cases  we  must  admit  certain  elements  of  sensitization.  In  Wolff 
Eisner's  recent  discussion  one  finds  the  admission  that  the  tuberculous 
individual  presents  a  definite  hypersusceptibility  to  a  number  of  pro- 
teins of  nontuberculous  origin  so  that  asthmatic  phenomena  in  tuber- 
culous individuals  are  to  be  expected.  So,  too,  in  the  true  asthmatic 
we  must  expect  that  attacks  will  be  precipitated  not  only  by  specific 
antigens  but  by  a  variety  of  metabolic  alterations  or  shocks  which 
may  bring  about  focal  activation  such  as  has  been  discussed  in  the 
chapter  of  focal  reactions.  During  pregnancy  asthma  may  become 
manifest  (Hepworth,  Salaberry),  although  as  a  rule  the  reverse  is 
more  common — that  is,  asthmatics  are  usually  free  from  attacks. 
Onset  of  attacks  after  remote  trauma  (Loeper  and  Codet)  or  psychic 
disturbances  are  common  examples  of  the  phenomenon. 

As  long  as  the  conviction  was  entertained  that  desensitization  was 
as  specific  as  sensitization,  efforts  at  therapy  naturally  centered  about 
the  determination  of  the  particular  protein  that  might  be  the  cause 
of  the  disease  and  the  endeavor  to  bring  about  an  increased  resistance 
or  tolerance  by  subcutaneous  injection  of  the  antigen.  Walker's 
publications  in  this  field  are  of  particular  importance.  Walker's 
method,  which  consists  of  desensitization  by  vaccination,  is  usually 
followed  by  quite  satisfactory  and  often  permanent  results. 

In  recording  observations  on  the  treatment  of  asthmatics  which 
were  sensitive  to  various  proteins  and  also  those  in  whom  no  specific 
sensitization  could  be  determined,  Walker  describes  the  therapeutic 
result  in  this  latter  group  of  150  patients  who  were  not  sensitive  to 
any  protein  with  which  they  were  tested.  It  may  be  well  to  quote 
Walker's  observations  in  full: 

"The  following  comparisons  as  regards  treatment  may  be  made 
between  sensitive  and  nonsensitive  asthmatic  patients.  In  the  previous 
article,  which  concerned  patients  sensitive  to  proteins,  and  in  the 

210 


MISCELLANEOUS  DISEASES  211 

first  part  of  this  article  which  concerns  patients  sensitive  to  bacterial 
proteins,  it  was  shown  that  in  general  a  favorable  prognosis  could  be 
anticipated  irrespective  of  the  age  of  onset  of  asthma  or  the  age  of 
the  patient  when  treated.  With  the  nonsensitive  patients,  however, 
the  later  the  age  of  onset  and  the  later  the  age  of  the  patient  when 
treatment  is  begun,  the  more  unfavorable  the  prognosis.  The  duration 
of  asthma  alone  played  little  part  in  the  prognosis  in  either  type  of 
case.  Seventy-five  per  cent,  of  the  sensitive  patients  were  relieved 
of  asthma  by  treatment  with  the  proteins  to  which  they  were  sensi- 
tive, whereas  only  40  per  cent,  of  the  nonsensitive  patients  were  re- 
lieved of  asthma  by  treatment  with  vaccines.  The  permanency  of 
relief  of  asthma  in  the  sensitive  patients  was  of  much  longer  duration 
than  in  the  nonsensitive  patients.  Both  the  sensitive  and  the  nonsen- 
sitive patients  illustrate  specificity  in  the  treatment  of  bronchial 
asthma;  that  is,  the  specificity  of  proteins  in  the  treatment  of  sensi- 
tive cases  and  the  specificity  of  bacteria  in  the  treatment  of  nonsensi- 
tive cases.  We  have,  however,  only  inferred  that  nonsensitive  asth- 
matic patients  are  not  benefited  by  treatment  with  proteins.  Because 
of  the  more  or  less  general  belief  that  infections  may  be  alleviated 
by  nonspecific  protein  therapy — and  in  the  case  of  chronic  arthritis 
this  is  frequently  found  to  be  true — it  seems  worth  while  to  mention 
our  results  in  the  treatment  of  the  infectious  or  nonsensitive  type  of 
bronchial  asthma  with  proteins. 

"Many  of  the  nonsensitive  or  infectious  type  of  asthmatics  have 
been  treated  with  various  proteins.  Three  patients  who  were  in  the 
hospital  wards  because  they  were  having  severe  asthma  every  day 
were  given,  intravenously,  typhoid  vaccine  without  improvement  in 
the  asthmatic  symptoms.  A  week  later  a  larger  dose  was  given 
without  any  benefit.  After  this  the  patients  were  given,  subcutane- 
ously,  two  hundred  million  autogenous  streptococcus  vaccine  made 
from  their  sputum  in  dextrose  bouillon.  A  few  days  later  one  patient 
was  somewhat  improved,  another  seemed  a  little  better  and  the  third 
was  not  improved.  A  week  later  still  the  autogenous  vaccine  was  in- 
creased to  250  million  and  a  few  days  after  this  one  patient  was  very 
much  better,  another  was  considerably  improved  and  the  third  was 
somewhat  better.  The  autogenous  vaccine  was  given  each  week  with 
gradual  improvement  in  each  instance  until  two  patients  left  the 
hospital  three  weeks  later  and  the  third  patient  was  able  to  leave 
in  five  weeks.  Therefore,  the  intravenous  typhoid  vaccine  was  fol- 
lowed by  no  benefit,  whereas  the  autogenous  streptococcus  vaccine  was 
followed  by  a  gradual  though  distinct  improvement.  Several  of  the 
nonsensitive  summer  asthmatics  and  some  of  the  other  nonsensitive 
cases  were  given  courses  of  treatment  with  various  pollen  without 
benefit.  A  few  nonsensitive  patients  were  given  wheat  proteins  and 
a  few  were  given  large  doses  of  peptone  subcutaneously  without  bene- 
fit. This  latter  method  of  treatment  is  dangerous  unless  the  patient 


212  PROTEIN  THERAPY 

is  tested  with  peptone  to  rule  out  the  possibility  of  his  being  sensitive 
to  it.  We  feel  that  this  fad  of  injecting  patients  with  proteins  to 
which  they  are  not  already  sensitive  is,  in  general,  apt  to  be  a  mis- 
take; the  possibility  of  sensitizing  patients  to  proteins,  exclusive  of 
typhoid  vaccine,  seems  to  outweigh  the  chance  of  improvement  by  such 
treatment." 

On  the  basis  of  the  fact  that  in  antianaphylasis  (or  desensitiza- 
tion)  a  nonspecific  element  is  at  times  observed,  other  methods  have 
been  devised  which  are  at  times  applied  more  easily  than  the  spe- 
cific methods  that  Walker  has  used.  Only  larger  clinical  experience 
will  enable  us  to  draw  conclusions.  It  must  be  borne  in  mind,  too,  that 
our  conception  of  protein  therapy  must  not  be  limited  to  the  intra- 
venous injection  of  typhoid  vaccine  or  peptone.  Many  of  the  milder 
reactions  continued  over  a  longer  period  of  time  may  be  found  much 
more  effective. 

Auld  has  reported  on  the  use  of  peptone  injections  (dissolved  in 
physiological  salt  solution  to  which  a  small  amount  of  sodium  car- 
bonate is  added)  given  either  intravenously  or  subcutaneously.  This 
treatment  has  been  instructive  in  respect  of  the  grouping  of  asthmatic 
cases.  Two  main  groups  occur  which  show  no  tendency  to  pass  into 
each  other.  One  group  comprises  such  as  quickly  respond  to  the 
treatment,  and  the  effect  is  more  or  less  lasting,  the  recurrences  being 
infrequent  and  milder  in  character.  The  other  group  is  resistant, 
and  is  subdivisible  into  such  as  are  totally  resistant  and  those  in  which, 
by  careful  immunization,  the  disease  may  be  largely  overcome. 
Pagniez  and  Widal,  Abrami  and  Brissaud  use  peptone  by  mouth  and 
Cordier  uses  peptone  enemas.  The  peptone  seems  to  be  polyvalent  for 
most  of  the  substances  causing  the  anaphylaxis.  Some  require  the 
continuous  use  of  the  peptone;  others  do  better  when  it  is  given  for 
three  to  eight  days  followed  by  an  interval  of  the  same  length.  By 
this  means  they  have  succeeded  in  curing  the  tendency  in  time  in 
many  cases,  the  time  required  for  complete  desensitization  depending, 
however,  on  the  personal  equation.  Other  observers  have  used  col- 
loidal metals  and  Boyd  reported  that  he  had  successfully  treated 
several  cases  of  asthma  with  typhoid  vaccine  (50  million  organisms 
intravenously).  Danysz  considers  that  the  intestinal  flora  furnish  the 
substrate  for  the  antigen  which  sensitizes  the  patient  in  asthma, 
in  certain  skin  and  gastro-intestinal  diseases.  In  an  antiphylactic 
treatment  he  uses  the  bacteria  isolated  from  the  stool  for  subcutaneous 
injection  with  apparently  good  results. 

Together  with  Miller  we  have  used  Intravenous  injections  with 
typhoid  vaccine  in  asthma  in  a  number  of  cases.  In  some  the  results 
were  quite  satisfactory,  in  others  there  was  no  apparent  effect  on 
the  attacks;  the  latter  group  including  particularly  the  cases  in  which 
food  sensitization  was  demonstrable.  It  is  possible  that  a  method  such 


MISCELLANEOUS  DISEASES  213 

as  that  of  turpentine  injections  might  be  more  satisfactory  because 
the  effect  is  prolonged  over  a  considerable  period  of  time. 

Sterling  has  reported  the  use  of  nonspecific  vegetable  proteins  in 
asthma ;  a  number  of  observers  have  reported  satisfactory  results  with 
endocrine  glands  of  various  types — ovarian  substance  (Fishberg), 
pituitrin  (Bensaude  and  Hallion,  Zueblin),  as  well  as  with  normal 
horse  serum  (Zener)  and  the  various  antitoxins — diphtheria  and 
tetanus.  Danysz  has  discussed  the  general  theory  of  antianaphylaxis 
or  desensitization  in  a  recent  paper  in  connection  with  related  dis- 
eases due  to  manifestations  of  hypersensitization  in  the  skin  and 
gastro-intestinal  tract. 

The  indiscriminate  use  of  sera  of  various  kinds  in  asthmatics  is  a 
practice  that  should  be  discouraged  because  a  number  of  deaths  have 
been  reported  as  a  result  of  such  injections.  (Boughton.)  It  must 
be  borne  in  mind  that  in  this  condition  we  are  dealing  with  a  patient 
highly  sensitive  to  protein  shock  and  great  care  should  be  exercised. 

ANGIONEUROTIC  EDEMA 

Schulmann  relates  that  discovery  of  a  transient  phase  of 
hemolysis,  the  crise  hemoclasique,  in  a  number  of  cases  of 
Quincke's  disease  has  confirmed  its  analogy  with  other  affec- 
tions in  which  anaphylaxis  is  a  factor,  and  treatment  on  this  assump- 
tion is  proving  successful.  He  applies  it  in  the  form  of  autohemo- 
therapy,  drawing  2  c.c.  of  blood  into  a  syringe  from  a  vein  at  the  bend 
of  the  elbow,  and  he  reinjects  the  blood  into  the  neighboring  sub- 
cutaneous tissue,  merely  drawing  the  needle  out  of  the  vein  and  point- 
ing the  tip  in  another  direction  in  the  tissues  of  the  arm.  He  has  made 
hundreds  of  these  injections  and  never  had  a  mishap,  but  the  desensi- 
tization may  take  up  to  two  months,  although  there  is  relief  almost 
from  the  first.  Three  typical  cases  are  described;  one  woman  of  31 
had  been  subject  to  attacks  of  angioneurotic  edema  since  before 
puberty,  returning  at  different  points  and  lately  becoming  more  fre- 
quent and  lasting  for  three  or  four  days.  She  was  given  three  in- 
jections a  week  and  by  the  end  of  the  third  month  the  tendency  seemed 
to  have  been  arrested.  She  returns  every  three  or  four  months  to 
have  a  few  injections  of  the  kind  made.  In  another  case  the  attacks 
had  been  recurring  every  two  or  three  days  during  the  six  months 
following  a  childbirth,  and  they  were  accompanied  with  headache  and 
urticaria.  There  has  been  no  recurrence  during  the  year  since  the 
course  of  thirty-five  injections. 

SECONDARY  ANEMIA 

A  number  of  observers  claim  to  have  obtained  satisfactory  stimu- 
lation of  the  hematopoietic  system  following  nonspecific  injection, 


214  PROTEIN  THERAPY 

particularly  milk,  and  have  used  it  in  the  treatment  of  anemia.  Thus 
Miiller  describes  its  use  in  the  treatment  of  secondary  anemia. 

In  pernicious  anemia  Grote  obtained  fair  results  with  the  injection 
of  milk,  one  case  increasing  in  blood  count  over  900,000  in  a  period 
of  8  days.  As  a  rule  he  obtained  little  febrile  reaction  after  the  in- 
jections, contrary  to  the  experiences  of  Schmidt  in  this  class  of  cases. 
Miiller  claims  to  have  had  favorable  results  in  bringing  about  re- 
missions after  milk  injections  (aolan)  which  increased  the  blood 
count  and  brought  about  an  increased  feeling  of  well  being  on  the 
part  of  the  patient. 

Hollaender  as  well  as  Fischer  reports  some  success  with  collargol 
injections.  The  effect  is  never  a  permanent  one. 

HEMORRHAGIC  DIATHESIS 

Dollken  has  devoted  considerable  attention  to  the  effect  of  non- 
specific therapy  on  blood  diseases.  That  serum  injections  of  various 
kinds  have  been  found  useful,  indeed  have  in  many  instances  been 
our  only  resource  in  the  hemorrhagic  diseases  is,  of  course,  well  known 
and  the  literature  is  readily  accessible  so  that  it  will  not  be  nec- 
essary to  enter  into  a  discussion  of  it  at  this  time.  (P.  Emile  Weil, 
Chalier,  Kurtz,  Lewisohn,  Berghausen,  Know,  Peterson.)  * 

Dollken  assumes  that  the  bleeding  in  purpura  is  largely  due  to 
two  factors — an  increased  fragility  of  the  blood  vessels  and  the  altera- 
tion in  the  blood  coagulability  whereby  it  does  not  clot  while  in  con- 
tact with  the  tissues.  Perhaps  when  once  shed  the  blood  may  show 
some  delay  in  coagulation,  but  Klinger  and  others  have  denied  this. 
Dollken  considers  the  alteration  in  the  platelet  count  as  a  symptom 
rather  than  a  causative  factor  because  in  cases  that  have  been  long 
cured  he  has  observed  that  the  diminution  in  the  platelet  count  may 
persist. 

The  leukocytosis  of  spontaneous  fever,  following  vaccine  injec- 
tion, and  following  the  intravenous  injection  of  deutero-albumose  has 
practically  no  effect  on  the  outcome  or  course  of  a  purpura,  the  stimu- 
lation of  the  spleen  and  bone  marrow  that  is  involved  seems  insuffi- 
cient to  alter  the  disease  process.  (See  also  the  paper  of  Radovici  and 
lagnov.) 

On  the  other  hand,  milk  injections  seem  to  have  a  particular  effect 
on  the  blood  vessels  of  smaller  caliber  and  on  the  coagulation 

*The  effects  of  the  serum  injection  are  possibly  due  to  the  alterations  in 
the  amount  of  fibrinogen  and  thrombokinase  that  follow  nonspecific  injections 
of  various  kinds.  Moll  observed  this  increase  and  von  den  Velden,  and  Lowy 
have  confirmed  it  for  gelatin,  serum,  peptones  and  parenterally  injected  proteins 
in  general.  Moderakowski  and  Orator  also  studied  the  effect  on  fibrinogen  and 
confirmed  the  previous  workers.  Wohlgemut  has  in  a  very  recent  paper  demon- 
strated that  the  increase  in  fibrinogen  probably  results  from  liver  stimulation, 
but  that  the  thrombokinase  arises  elsewhere. 


MISCELLANEOUS  DISEASES  215 

mechanism,  the  styptic  effect  being  very  apparent.  Thrombokinase  as 
well  as  fibrinogen  are  increased  and  the  permeability  of  the  capil- 
laries altered,  small  doses  seeming  to  increase  the  permeability,  larger 
ones  to  diminish  it. 

Dollken  therefore  decided  to  use  milk  in  cases  of  purpura  and  was 
surprised  to  observe  the  rapidity  of  the  effect  on  the  disease.  He 
made  injections  of  about  5  c.c.  every  three  days,  intramuscularly. 
There  was  little  inconvenience;  on  the  contrary,  a  marked  euphoria 
was  observed  after  the  injections.  In  only  one  instance  did  a  hema- 
toma  appear  at  the  site  of  the  injection  and  this  disappeared  after  24 
hours. 

Bleeding  into  the  tissues  stopped  5  hours  after  the  injection,  a 
most  interesting  feature  being  the  observation  that  this  clinical  re- 
sult was  manifest  without  effect  on  the  number  of  the  blood  platelets 
in  the  circulation.  The  permeability  of  the  vessels  does  not  seem 
to  be  altered  as  rapidly  as  the  effect  on  the  coagulation  mechanism, 
because  small  petechiaB  were  noted  to  appear  until  about  24  hours 
after  the  injection. 

The  resorption  of  blood  from  the  tissues  commenced  promptly  after 
the  alterations  in  coagulation  had  taken  place.  After  from  7  to  8 
hours  small  hemorrhages  in  the  mucous  membranes  of  the  mouth 
could  be  observed  to  be  decreasing  in  size;  in  another  8  to  10  hours 
the  smaller  ones  had  disappeared  and  the  larger  areas  showed  con- 
siderable retrogressive  change.  Large  areas  of  bleeding  showed  a 
broad  yellow  band  of  discoloration  from  1  to  2  c.c.  wide  around  the 
margin  in  from  18  to  24  hours  where  regression  had  occurred,  and 
the  tension  of  the  hematomas  was  lessened. 

Dollken  details  his  experience  in  one  severe  case  of  purpura.  The 
patient  bled  two  hours  from  a  small  skin  abrasion,  and  the  bleeding 
recommenced  on  the  slightest  renewed  trauma  to  the  scab.  The  paraf- 
fined blood  coagulated  in  9  minutes.  Deutero-albumose  (.05  gm.  in- 
travenously) merely  increased  the  bleeding  that  had  occurred  from  a 
small  skin  puncture  from  the  ear  for  several  days.  The  following  day 
a  puncture  still  bled  for  14  hours;  the  paraffined  blood  coagulated 
in  14  minutes.  During  this  time  numerous  fresh  areas  of  hemorrhage 
had  been  observed  over  the  body.  The  patient  was  then  given  5  c.c. 
milk  intramuscularly.  In  5  hours  all  bleeding  ceased.  After  8 
hours  the  petechiae  in  the  mucous  membrane  of  the  mouth  were  de- 
creasing in  size.  Bleeding  from  a  new  skin  puncture  in  the  ear  lobe 
now  ceased  in  20  minutes  and  the  paraffined  blood  coagulated  in 
8%  minutes.  Platelets  were  absent  during  the  entire  clinical  change. 
Leukocytosis  was  moderate.  All  cases  that  had  albuminuria  before- 
hand showed  clear,  albumin- free  urine  after  the  injections. 

Bosanyi  has  found  that  intravenous  injections  of  salt  solution 
have  given  him  results  that  are  more  satisfactory  in  purpura  simplex, 
morbus  Werlhofii  and  hemophilia  than  any  other  method  that  he  had 


216  PROTEIN  THERAPY 

employed.  He  describes  the  result  obtained  in  7  cases,  the  first  two 
of  which  received  injections  of  5  c.c.  of  3%  salt  solution.  Later 
he  used  larger  doses  (about  10  c.c.  of  a  5%  solution)  and  with  these 
the  results  were  striking.  The  bleeding  usually  ceased  after  a  few 
hours.  Injections,  given  daily,  were  without  reaction  on  the  part  of 
the  patient.  He  is  under  the  impression  that  the  result  on  coagula- 
tion is  due  to  the  reversal  of  the  exchange  between  the  capillaries 
and  tissues  so  that  there  is  an  actual  imbibition  of  "tissue  fluid"  and 
coagulating  accelerating  substances  from  the  tissues  by  the  blood 
stream,  based  on  the  work  of  von  den  Velden. 

Vines  would  effect  hemorrhagic  conditions  by  means  of  anaphy- 
lactic  shock  effects  or  sensitization.  Vines  bases  his  method  on  the 
following  considerations : 

The  intradermal  reaction  is  a  modified  form  of  anaphylactic  shock 
of  general  as  well  as  of  local  significance,  in  which  the  stimula- 
tion of  the  thrombogenetic  functions  of  the  somatic  cells  is  a  salient 
feature.  The  changes  in  coagulability  of  the  blood  in  anaphylactic 
shock  occur  in  two  stages:  a  period  of  acceleration  which  occurs 
early,  followed  by  a  period  of  retardation;  further,  that  the  predomi- 
nance of  the  former  or  the  latter  depends  on  the  lesser  or  greater 
severity  of  the  shock.  The  intoxicating  injection  in  a  sensitized 
individual  may  act  as  a  catalytic  agent  in  inducing  the  intracellular 
reactions  which  constitute  the  anaphylactic  phenomena.  In  cases  of 
hemophilia,  Vines  says,  the  duration  of  the  effect  of  the  intradermal 
reaction  is  dependent  on  the  duration  of  the  anaphylactic  period.  But 
the  shorter  or  longer  duration  of  this  effect  is  also  directly  dependent  on 
the  greater  or  lesser  severity  of  the  hemophilic  condition. 

He  describes  3  cases  so  treated,  all  being  sensitized  to  sheep  serum 
and  small  doses  of  sheep  serum  injected  interdermally  after  sensitiza- 
tion. In  the  first  two  cases  the  second  injection  caused  an  increase  in 
the  blood  clotting  rate  of  the  individual,  which  was  evidently  quite 
permanent,  in  the  third  case  the  effect  was  less  apparent.  Confirm- 
ing Vines'  observations,  Rouchetti  reports  two  severe  cases  of  hemor- 
rhagic purpura  which  abruptly  subsided  when  serum  sickness,  with 
urticaria,  followed  an  injection  by  the  vein  of  normal  horse  serum 
or  of  serum  from  the  emulgent  vein  of  goats.  A  similar  method 
to  stop  bleeding  after  operation  has  been  used  by  Neirotti  and  Viola. 
Neirotti  and  Viola  report  two  cases  of  persisting  hemorrhages  after  a 
minor  operation,  finally  arrested  by  the  anaphylactic  shock  from  the 
subcutaneous  injection  of  normal  horse  serum,  eighteen  hours  after 
a  preliminary  injection  of  10  c.c. 

Voight  treated  several  cases  of  scurvy  with  milk  injections  and 
noted  a  prompt  styptic  effect,  as  well  as  general  improvement  of  the 
patients. 


MISCELLANEOUS  DISEASES  217 

NEPHRITIS 

The  albuminuria  that  accompanies  many  acute  febrile  diseases 
is  very  promptly  influenced  by  nonspecific  injections,  according  to  a 
number  of  observers. 

Treatment  of  a  case  of  pyelonephritis  has  been  reported  by  Gow, 
who  in  this  instance  made  use  of  a  colon-like  organism  for  intra- 
venous injections.  A  chill  was  invariably  produced  in  about  3  to 
3%  hours;  there  were  nausea  and  headache  and  the  temperature  rise 
usually  wert  to  103°  F.  or  104°  F.  This  organism  was  at  first  used 
in  a  dosage  of  50;  later  75  and  125  million  were  injected  but  the 
severity  of  the  reaction  diminished  with  successive  injections.  Thus 
when  the  dosage  of  75  million  was  injected  the  reaction  was  only 
to  101.6°  F.  with  some  cutaneous  hyperesthesia  and  yawning  on  the 
part  of  the  patient.  This  case  of  pyelonephrosis  made  a  complete 
recovery. 

In  colon  and  staphylococcus  pyelitis  with  concomitant  bladder 
irritation  Karo  has  reported  very  favorable  results  with  injections  of 
terpichin.  Similarly  in  staphylococcus  infections  of  the  urinary  tract 
and  in  the  cholecystitis  of  children  the  results  have  been  satisfactory. 
In  cases  of  simple  bacteriuria,  however,  no  results  were  obtained.  In 
the  cystitis  that  accompanies  enlarged  prostate  glands  the  injections 
were  also  found  useful. 

NEURITIS 

Dollken  has  prepared  an  autolysate  of  staphylococci  and  bacillus 
prodigiosus  which  has  been  used  rather  extensively  and  is  distributed 
commercially  under  the  name  of  "vaccinurin."  Dollken  tried  out  a 
series  of  bacterial  extracts,  including  tuberculin,  and  vaccines  in 
neuritis  and  concluded  that  the  combination  above  mentioned  was 
followed  by  the  best  results.  From  his  work  he  was  led  to  the  belief 
that  in  heterovaccination  we  do  not  deal  wholly  with  a  nonspecific 
plasmaactivation  but  that  there  existed  a  degree  of  selectivity  in  the 
effect  of  the  different  vaccines,  that  is,  they  were  more  or  less  organo- 
tropic. 

In  the  first  series  of  neuritic  processes  (51  cases)  treated  by  him 
are  included  both  trigeminal  and  intercostal  neuralgia,  sciatica,  and 
a  large  number  of  neuritides  of  varying  etiology — cold,  professional, 
alcoholic,  post-typhoidal,  luetic,  diphtheritic,  pressure,  facial  and 
radial.  He  observes  that  the  pressure  neuralgias  and  the  «so-called 
rheumatic  palsies  were  the  ones  most  easily  influenced. 

Holtzl  reports  the  treatment  of  some  90  cases  with  vaccinurin. 
Of  these  61  made  complete  recoveries  and  28  were  improved.  The 
series  included  25  cases  of  sciatica  of  whom  16  made  .prompt  and  com- 
plete recoveries.  The  injection  was  followed  by -a  systemic  effect  and 


218  PROTEIN  THERAPY 

the  maximum  therapeutic  effect  was  observed  in  about  6  hours 
after  the  injection. 

Cadbury  has  described  the  results  obtained  with  typhoid  vac- 
cines in  a  group  of  cases  with  neuritic  pains  due  to  a  variety  of 
causes.  These  included  one  carcinoma  of  the  breast,  in  which  there 
was  temporary  relief  from  pain;  four  gunshot  injuries,  all  of  which 
were  cured;  one  fibroid  phthisis  which  was  relieved,  1  tic  douloureux 
which  was  improved  for  6  months,  etc. 

Boyd  also  reports  the  successful  treatment  of  neuritis  with  mod- 
erate doses  of  typhoid  vaccine  intravenously. 

Following  nonspecific  injections  in  neuritides  a  distinct  focal  re- 
action may  become  manifest.  There  may  be  a  transient  increase  in 
the  pain  and  other  manifestations  of  the  lesion  that  reaches  its  max- 
imum in  from  4-8  hours,  depending  on  the  method  used  to  elicit  the 
reaction,  followed  by  an  analgesia  which  in  some  instances  may  be 
transient,  in  others  permanent  in  character. 

Wishura  using  "vaccinurin"  found  that  neither  the  focal  nor  the 
general  reactions  were  very  severe.  In  severe  degenerative  inflam- 
mation of  nerve  trunks  as  well  as  in  the  more  common  joint  neuroses 
the  injections  were  very  successful. 

EAR  AFFECTIONS 

Rauch  reports  the  results  of  milk  injections  (5  c.c)  in  41  cases 
of  acute  middle  ear  infections.  According  to  his  series  the  results 
were  very  favorable,  only  three  of  the  cases  requiring  operative  in- 
terference. Gomperz,  on  the  other  hand,  obtained  no  satisfactory 
results  and  Hirsch,  who  used  turpentine  injections  in  cases  of  furuncu- 
losis  and  eczema  of  the  meatus,  as  well  as  in  acute  and  chronic  sup- 
purative  conditions  of  the  ear,  obtained  entirely  negative  results. 

The  first  report  on  the  subject  was  that  of  Alexander,  who  has 
described  his  results  in  ear  diseases  and  sinus  infections ;  later  Lawner 
reported  some  cases  of  middle  ear  disease  treated  with  milk  injections 
with  excellent  results. 

MALIGNANT  NEOPLASMS 

A  number  of  procedures  and  "cures"  for  both  carcinoma  and 
sarcoma  have  been  advocated  during  the  course  of  more  recent  years 
which  have  had  as  the  basis  of  their  mechanism  the  alterations  which 
we  now  recognize  as  due  to  nonspecific  stimulation.  I  need  but  re- 
call the  treatment  of  cancer  with  trypsin  and  amylopsin  injections 
by  Beard  and  the  treatment  of  sarcoma  by  the  injection  of  Coley's 
fluid,  a  bacterial  autolysate;  or  the  use  of  tumor  autolysates  or  serum 
(Lewin)  for  purposes  of  immunization.  These  and  all  other  methods 
that  provoke  a  similar  systemic  response  are  followed  by  one  of 
two  reactions  on  the  part  of  the  patient. 


MISCELLANEOUS  DISEASES  219 

When  the  tumor  is  small,  not  necrotic  or  ulcerated,  there  may  re- 
sult little  or  no  temperature  reaction  or  malaise  following  the  in- 
jection and  relatively  little  local  effect.  There  may  be  a  slight  increase 
in  pain  at  the  focus  and  some  evidence  of  an  increased  inflammatory 
reaction,  but  the  size  of  the  tumor  will  not  alter  materially.  In- 
deed at  times  the  rate  of  growth  is  increased. 

When  we  deal  with  a  large  tumor  mass,  with  either  central  necrosis 
or  ulceration,  nonspecific  injections  are  as  a  rule  followed  by  a  de- 
cided rise  in  the  temperature  and  a  feeling  of  malaise.  The  further 
course  will  be  determined  by  the  effect  on  the  local  pathology.  There 
is  usually  a  marked  increase  in  the  pain  and  evidence  of  inflammation, 
digestion  takes  place  of  the  necrotic  material  and  the  tumor  may  be- 
come apparently  smaller  in  size.  The  general  condition  of  the  pa- 
tient at  this  time  will  vary  with  the  amount  of  the  protein  split 
products  which  are  absorbed.  If  large  in  amount  and  but  partially 
digested,  the  temperature  will  continue  high  for  a  period  of  several 
days;  if  small  in  amount,  or  if  more  completely  digested  at  the  focus 
before  absorption,  then  the  temperature  reaction  may  fall  within  the 
limits  of  the  provocative  temperature  of  the  nonspecific  agent  injected. 
In  either  case,  in  the  period  of  recovery  from  the  nonspecific  re- 
action and  from  the  reaction  caused  by  the  absorption  of  the  auto- 
lytic  tumor  products,  the  balance  swings  to  the  reparative  side  and 
a  general  euphoria  with  increased  appetite,  lessened  pain  and  ir- 
ritability, improved  nutrition  and  feeling  of  strength  may  set  in 
which  will  last  for  a  variable  period.  If  a  diminution  of  the  size  of 
the  tumor  (because  of  the  digestion  of  necrotic  material)  has  oc- 
curred at  the  same  time,  the  natural  inference  of  curative  effects 
are  prone  to  further  encourage  both  the  patient  and  the  physician. 
This  clinical  reaction  has  been  the  basis  of  practically  all  of  the 
methods  of  therapy  which  have  at  various  and  sundry  times  been  re- 
ported and  it  is  quite  possible  that  it  takes  a  part  in  the  reaction 
that  follows  after  Roentgen  and  radium  treatment,  although  by  no 
means  must  it  be  held  accountable  for  all  the  effect  there  achieved. 

We  cannot  avoid  the  conclusion  that  the  nonspecific  reaction  has 
little  or  no  effect  on  the  rate  of  growth  of  the  malignant  tissue  as 
long  as  it  is  well  supplied  with  vascular  connections.  Once  the 
tumor  cells  become  necrotic  or  perhaps  undergo  some  of  the  earlier  de- 
generative changes,  digestive  stimulation  such  as  that  which  follows 
nonspecific  therapy  has  an  apparent  effect  similar  in  character  and 
range  to  that  observed  in  other  pathological  conditions. 

On  repeated  injections  the  effect  becomes  less  manifest  and  the 
reaction  usually  less  severe,  depending,  of  course,  on  the  amount  of 
necrosis  present  in  the  tumor.  One  finds  that  not  only  the  commonly 
used  nonspecific  agents,  but  even  iodin  injections  are  followed  by 
alterations  in  the  tumor  and  a  febrile  reaction  due  to  focal  diges- 
tion. Moresowa  has  demonstrated  this  fact  in  a  series  of  cases. 


220  PROTEIN  THERAPY 

The  recent  experimental  work  of  Murphy  and  others  dealing  *with 
the  lymphocyte  as  a  factor  in  resistance  to  malignant  infiltration  is 
one  that  is  not  involved  in  the  nonspecific  reaction  here  described  be- 
cause the  lymphocytic  reaction  after  such  injections  is  negligible. 
Miiller  has,  however,  called  attention  to  the  fact  that  epithelial  tis- 
sues— he  observed  new  formed  epithelial  bridges  covering  granulation 
tissue — seemed  particularly  susceptible  to  the  digestive  changes  in- 
duced by  milk  injections,  etc. 

A  different  course  of  procedure  has  been  adopted  by  Opitz  and 
Friederich  in  trying  to  use  the  nonspecific  reaction  in  conjunction  with 
the  Roentgen  irradiation.  While  their  result  is  merely  experimental, 
it  offers  at  least  the  possibility  of  development. 

In  their  studies  on  the  treatment  of  carcinoma  by  means  of 
Roentgen  irradiation  and  radium  they  soon  came  to  realize  that  the 
growth  does  not  depend  wholly  on  the  inherent  rate  of  the  tumor  cell 
growth  but  on  the  resistance  of  the  tissues  that  were  the  seat  of  the 
malignant  invasion.  This  varies  not  only  with  individuals  but  under 
certain  physiological  conditions  as  well.  v.  Groff,  as  well  as  Slye, 
have,  for  instance,  called  attention  to  the  depression  of  the  rate  of 
tumor  growth  in  mice  during  pregnancy,  and  while  Slye  seems  to  con- 
sider the  increased  metabolic  demands  of  the  maternal  and  fetal 
organisms  responsible  for  this  inhibition  on  the  rate  of  tumor  growth, 
other  factors  possibly  enter  into  the  mechanism. 

A  similar  depression  in  the  rate  of  growth  may  be  observed  at 
times  during  the  course  of  infectious  diseases,  after  serum  injections 
and  other  related  procedures  where  we  find  an  increase  in  the  anti- 
ferment  of  the  serum  and  a  resulting  tendency  for  the  protection  of 
connective  tissue  and  a  depression  of  the  protein  metabolism  that  fol- 
lows after  all  these  nonspecific  alterations.  Of  course,  during  the  acute 
shock  effects — either  in  infectious  diseases  or  after  nonspecific  injec- 
tions, or  after  parturition — when  proteolytic  enzymes  are  mobilized, 
marked  digestive  phenomena  may  be  observed  at  the  site  of  the 
malignant  invasions  but  this  usually  concerns  the  digestion  of  tissue 
already  necrotic,  or  of  connective  tissue  hyperplasias. 

Bergel  has  reported  observations  concerning  the  acceleration  growth 
of  bony  tissue  after  nonspecific  injections  and  Hoke,  Doberauer  and 
Pittroff  saw  a  similar  effect  on  connective  tissue.  Opitz  and  Fried- 
erich proceeded  to  make  use  of  this  principle  in  their  work  with 
Roentgen  rays.  Assuming  that  after  irradiation  the  connective  tissue 
cells  were  to  a  degree  fatigued,  by  nonspecific  injections  these  cells 
might  be  stimulated  and  the  fatigue  so  overcome.  On  this  basis  these 
rejuvenated  cells  would  then  react  like  young  cells  and  an  atreptic  im- 
munity would  be  established;  the  carcinoma  cells  would  die  of  inani- 
tion, would  be  "strangulated"  and  become  necrotic. 

While  their  results  are  not  extended  enough  to  warrant  any  con- 
clusions they  state  that  they  were  encouraging.  Warnekros  is  said 


MISCELLANEOUS  DISEASES  221 

to  have  combined  serum  injections  with  Roentgen  rays  in  a  similar 
manner  of  treatment. 


PEDIATRICS 

Slawik  has  reported  on  the  treatment  of  infants  with  nonspecific 
therapy,  using  human  milk  injected  intramuscularly  in  doses  from  1 
to  5  c.c.  usually  in  two-day  intervals.  In  most  cases  the  milk  was 
first  boiled;  in  a  few  cases  he  used  the  raw  milk  without  encounter- 
ing any  ill  effects. 

Slawik  found  that  the  reaction  obtained  was  independent  of  the 
age  of  the  child,  but  was  influenced  by  the  state  of  nutrition,  that  is, 
the  vitality  of  the  patient,  by  the  feeding,  and  to  some  extent  by 
the  particular  disease  process  from  which  the  child  was  suffering. 
There  were  no  ill  effects  from  the  injections  and  when  for  purposes  of 
comparison  healthy  infants  were  treated  with  injections  of  similar 
amounts  there  was  no  alteration  in  the  weight  curve.  With  repeated 
injections  the  reactions  became  less  intense  and  Slawik  calls  atten- 
tion to  the  well-known  fact  that  humans  are  normally  relatively  re- 
sistant to  anaphylactic  sensitization  so  that  the  danger  from  this 
source  snould  not  be  overestimated. 

Among  the  26  cases  treated  by  him  were  the  following: 

3  ophthalmoblennorrhea.  These  were  followed  by  a  decided  focal 
reaction;  one  improved  at  once,  the  others  after  repeated  injections. 

3  erysipelas.    1  improved  at  once,  one  after  three  weeks,  the  other 
case  became  chronic  and  later  developed  meningitis. 

4  of  multiple  abscesses.    These  were  healed  in  from  7  to  10  days. 

1  phlegmon  in  a  marantic  child.    The  general  condition  improved 
after  the  injections  and,  despite  the  continued  cachexia,  the  phlegmon 
healed. 

2  marantic  infants.    One  of  these  with  thrush;  this  infant  became 
more  agile,  drank  better  and  recovered.    The  other  was  not  altered. 

3  with  chronic  exudative  diathesis;  they  were  not  altered. 

6  severe  dysenteries,  of  whom  4  died.  After  the  injections  a  very 
high  agglutinin  titer  was  observed  in  all  the  cases. 

In  a  later  series  Slawik  injected  infants  parenterally  with  white  of 
egg,  breast  milk  or  other  substances  in  treatment  of  various  pathologic 
conditions.  The  results  were  disappointing,  probably  on  account  of  the 
inadequate  development  of  the  defensive  forces  at  this  age.  Actual 
benefit  was  realized  only  with  pyodermatitis  and  gonococcus  infection. 

Langer  has  studied  particularly  the  furunculosis  of  infants.  He 
noted  that  after  the  injection  of  various  vaccines,  no  matter  what 
the  clinical  result,  there  was  little  or  no  antibody  response.  As  a 
result  he  decided  that  the  clinical  benefit  could  not  be  a  specific  one 


222  PROTEIN  THERAPY 

and  that  he  might  just  as  well  discard  the  old  idea  of  a  negative  phase 
and  the  interval  dosage  as  formerly  used.  He  therefore  gave  large 
doses  (500  to  1,000  million)  of  staphylococcus  vaccine  (opsonogen) 
intramuscularly.  Injections  were  made  daily,  usually  two  or  three 
injections  sufficing  to  bring  the  disease  process  to  a  standstill  and 
the  recovery  of  the  patient  usually  followed  in  a  short  time.  When- 
ever phlegmons  existed  they  were  of  course  opened  and  drained. 

The  vulvovaginitis  of  infants  and  children  does  not  yield  to  non- 
specific therapy  (collargol — Vollbrandt). 

Normal  horse  serum  has  been  used  successfully  as  a  stimulant  in 
poorly  developed  infants  by  Ferreira.  It  seems  to  whip  up  the  slug- 
gish metabolism  and  nutrition  in  general  so  that  the  child  afterward 
progresses  more  or  less  normally.  He  injected  it  in  three  cases  here 
described.  One  of  the  infants  weighed  only  3,750  gm.  at  the  tenth 
month  when  the  serotherapy  was  started,  and  the  benefit  was  so 
unmistakable  that  it  was  kept  up  for  sixteen  months,  the  child  having 
thus  been  given  2,386  gm.  of  the  serum,  and  its  weight  showing  a 
regular  increase.  He  began  with  2.5  c.c.  but  soon  reached  the  dose  of 
20  c.c.,  repeated  two  or  three  times  a  week.  A  3  months'  babe  im- 
proved so  rapidly  after  the  serotherapy  was  begun  that  the  latter 
could  soon  be  dropped,  the  improvement  continuing  thereafter.  None 
of  the  three  infants  was  entirely  breast  fed.  Rinz  has  reported  similar 
cases. 

Czerny  and  Eliasberg  have  used  this  effect  of  nonspecific  therapy 
to  stimulate  the  general  condition  of  children  ill  with  tuberculosis. 
In  26  cases  so  treated  (daily  injections  of  normal  horse  serum  in 
doses  up  to  2  c.c.)  9  died;  in  12  there  was  remarkable  improvement 
despite  the  fact  that  some  of  the  cases  were  tuberculosis  of  the  peri- 
toneum and  of  the  lungs. 

Valagussa  has  made  a  careful  study  of  protein  therapy  in  acute 
diseases  in  children  and  in  his  report  reproduces  the  temperature 
curves  of  the  various  groups  treated  with  different  proteins.  In  51 
children  from  14  months  to  12  years  old,  all  with  typhoid  fever,  the 
intramuscular  injection  of  peptone  according  to  Nolf  had  a  very  fa- 
vorable influence  on  the  course  of  the  disease  in  the  majority.  In  31 
cases  of  influenza  in  children,  he  injected  various  serums  and  anti- 
serums,  and  when  this  serotherapy  was  early,  intense  and  continued, 
the  results  were  excellent.  There  were  only  3  deaths  in  this  group  of 
31  severe  cases  of  influenza.  His  experimental  research  on  the  au- 
tolysates  of  beer  yeast  in  colloidal  suspension  confirmed  their  efficacy 
in  increasing  opsonins,  etc.,  and  this  was  sustained  in  33  cases  of  pneu- 
monia or  typhoid  while  no  effect  was  apparent  in  3  cases  of  whoop- 
ing cough. 

The  three  types  of  antigens  represented  by  peptone,  horse  serum 
and  organized  ferments  behave  alike;  the  only  difference  is  in  the  in- 
tensity of  the  phenomena  induced.  The  yeast  autolysates  are  the 


MISCELLANEOUS  DISEASES  223 

weakest  and  slowest  in  their  action,  but  all  serve  to  reenforce  the 
organism  in  its  fight  against  the  infection.  There  are  no  symptoms 
of  anaphylaxis  with  the  yeast,  aside  from  the  local  reaction,  and  the 
effect  on  the  temperature,  and  he  commends  this  as  a  harmless  means 
to  activate  and  augment  the  kataphylactic  powers  of  the  organism 
in  any  and  every  bacterial  infection.  "With  this  extract  of  the  cells 
of  the  saccharomyces  we  provide  a  poly-antigen  therapy,  and  we  can- 
not go  amiss  in  treating  a  disease  by  augmenting  the  natural  index  of 
resistance  and  the  defensive  forces." 

The  largest  series  of  infants  has  been  treated  by  Plantenga  (300 
cases).  These  included  various  mar  antic  infants,  usually  with  ali- 
mentary intoxication.  He  injected  as  a  rule  some  30  c.c  of  an  "anti- 
colon"  serum  obtained  by  immunizing  animals  against  colon  bacilli. 
The  results  were  quite  remarkable. 

More  recently  Putzig  has  also  described  a  number  of  cases.  He 
found  that  serum  injections  (he  used  diphtheria  antitoxin)  in  ma- 
rantic  children  caused  an  increase  in  weight  and  an  improvement  in 
the  general  condition  and  that  this  improvement  was  not  a  temporary 
affair  (due  to  water  retention,  etc.),  but  was  due  to  a  stimulation  of 
the  body  tissues  and  an  actual  growth  of  tissues.  Of  7  cases  5  were 
appreciably  improved. 


CHAPTER  XIV 
TREATMENT  OF  GENERAL  PARALYSIS,  TABES,  ETC. 

While  the  etiological  significance  of  the  Spirocheta  pallida  in  its 
relation  to  tabes  and  general  paralysis  has  been  firmly  established, 
the  therapy  of  these  diseases  has  never  been  very  satisfactory, 
despite  the  development  of  our  more  intensive  methods  of  mercurial 
treatment  and  the  intravenous  and  intraspinal  application  of 
salvarsan.  The  damage  once  done  the  central  nervous  system  is  ir- 
reparable and  the  problem  of  therapy  resolves  itself  largely  in  pre- 
venting progress  of  the  disease  rather  than  with  the  thought  of  re- 
covery. Even  this  modest  result  is  seldom  achieved.  Remissions 
are  of  course  known  to  occur  spontaneously  during  the  course  of  the 
disease  and  this  fact  is  more  often  than  not  apt  to  bias  the  observer 
working  with  some  new  preparation  and  he  ascribes  therapeutic  ef- 
fects to  the  procedure  which  are  not  actually  due  to  the  remedy. 

GENERAL  PARALYSIS 

There  seems  little  doubt  of  the  clinical  observation  that  has  been 
made  by  numerous  observers  and  for  many  years  that  intercurrent 
infections  (malaria,  typhoid,  suppurative  processes,  etc.)  are  not 
uncommonly  followed  by  an  arrest  of  the  disease  process  and  even 
apparent  improvement  in  the  general  condition  of  the  patient  suffer- 
ing from  progressive  paralysis  (v.  Halban,  Marro  and  Ruata,  etc.). 

Very  early  efforts  to  make  use  of  this  knowledge  were  reported. 
Jacobi  in  1854  reported  on  the  use  of  artificial  abscesses  in  the  treat- 
ment of  general  paralysis  and  Meyer  in  1877  again  took  up  the 
method. 

Some  rather  illuminating  statistics  have  been  compiled  by  Mat- 
tauschek  and  Pilcz  in  this  connection.  They  found  that  in  4,134  cases 
of  syphilis  4.7%  developed  general  paralysis.  In  a  group  of  157 
of  the  luetic  cases  there  was  a  history  of  an  intercurrent  infection  such 
as  erysipelas,  pneumonia,  etc.;  not  a  single  case  of  general  paralysis 
developed  among  these.  While  by  no  means  free  from  criticism, 
they  nevertheless  confirm  to  some  extent  the  clinical  observations 
just  alluded  to. 

It  was  on  this  basis  that  v.  Jauregg  began  the  use  of  tuberculin  in 
the  treatment  of  general  paralysis;  tuberculin  being  selected  as  a 
pyrogenic  agent  because  of  its  availability  and  the  certainty  of  the 
febrile  reaction,  v.  Jauregg  had  first  tried  a  pyocyaneus  vaccine  in 

224 


TREATMENT  OF  GENERAL  PARALYSIS,  TABES,  ETC.    225 

a  series  of  acute  psychoses  with  results  that  encouraged  him  to  ex- 
tend his  experiments  to  other  forms  of  mental  disease.  His  associate, 
Boeck,  has  published  the  results  of  the  treatment  of  cases  of  general 
paralysis  in  v.  Jauregg's  clinic. 

Pilcz  continued  the  method.  He  gave  old  tuberculin  in  10% 
solution,  starting  the  treatment  with  0.01  gm.,  and  continuing  up  to 
0.5  gm.  Injections  were  made  every  two  days.  The  patients  re- 
acted with  a  temperature  up  to  about  101°  F.  and  there  was  an  as- 
sociated headache  and  lassitude.  Pilcz  noted  that  at  times  there  was 
an  increase  in  the  psychic  disturbance  at  the  time  of  the  reaction, 
but  this  usually  rapidly  disappeared. 

In  contrasting  a  series  of  66  treated  cases  with  66  not  treated 
the  mortality  was  20  and  39  respectively  during  the  first  year  under 
observation.  At  the  end  of  a  four-year  period  of  observation  8  of  the 
treated  group  were  still  living,  5  of  the  untreated. 

In  1911  Pilcz  published  a  further  series  of  86  cases,  which  were 
given  a  combined  treatment  of  potassium  iodid  and  tuberculin. 

Of  these  40%  did  not  respond  to  treatment; 

23%  were  arrested,  but  not  otherwise  improved; 
10%  became  fit  to  be  returned  to  normal  life;  and 
26%  were  restored  to  almost  normal  condition. 

In  1912  a  further  report  was  made.  At  this  time  26  were  still 
living,  12  of  them  occupationally  fit,  the  periods  of  remission  in  3 
cases  having  lasted  for  from  4  to  5  years,  in  15  cases  over  1  year. 

These  observers  used  tuberculin  because  it  was  convenient  to  ob- 
tain and  sure  in  its  effect.  They  observed  that  patients  who  seemed 
hypersensitive  to  tuberculin  and  reacted  violently  were  those  who 
derived  the  greatest  therapeutic  benefit  from  the  method. 

Hudovernig,  Battistessa,  Dollken,  Jukow  and  Joachim  confirmed 
these  findings. 

The  basic  theory  of  v.  Jauregg  was  that  the  therapeutic  effect 
in  paresis  was  due  to  the  increased  temperature.  The  work  of  Jahnel 
and  Weichbrodt — who  found  that  in  luetic  rabbits  subjected  several 
times  to  temperatures  of  from  42°  to  43°  C.  living  spirocheta  pallida 
could  no  longer  be  found  (other  spirochetes  were  not  so  susceptible 
to  high  temperatures) — is  of  particular  interest  in  this  connection. 
Donath  had  previously  used  salt  injections,  and  now,  with  other 
neurologists,  began  the  treatment  of  general  paralysis  with  leuko- 
cytic  stimulants,  considering  the  leukocytosis  thereby  obtained  as 
the  important  factor  of  benefit  to  the  patient.  Horbaczewski  having 
called  attention  in  the  early  nineties  that  nucleic  acid  (as  well  as 
pilocarpin  and  cinnamic  acid)  acted  as  powerful  leukocytic  stimu- 
lants, nucleins  were  applied  by  Fisher  and  by  Donath  in  the  treat- 
ment of  general  paralysis. 

Fisher's  first  series  contained  22  cases  so  treated  and  22  untreated 


226  PROTEIN  THERAPY 

cases  as  controls.  The  treatment  consisted  of  injections  of  one-half 
gram  nuclein  in  10%  solution.  The  average  duration  of  life  of  the 
treated  cases  was  15  months,  of  the  untreated  7  months.  Later  he 
treated  a  further  series,  this  time  with  larger  doses — from  %  to  3 
gm.  in  10%  solution  every  3  to  5  days.  Of  these  ten  were  treated, 
ten  untreated.  The  treated  cases  gave  5  remissions  (three  becoming 
progressively  active  again).  In  the  ten  control  cases  there  was  but 
one  remission,  that  following  a  long  continued  septic  condition. 

Donath  treated  21  cases  with  injections  every  5  or  7  days,  each 
injection  resulting  in  a  febrile  reaction  that  lasted  for  one  or  two 
days.  On  an  average  8  injections  were  given  the  patients;  the  leu- 
kocytic  reaction  was  quite  marked,  up  to  61,000  in  one  case.  Of 
these  cases  70%  showed  definite  evidence  of  improvement — in  47%' 
the  improvement  was  so  great  that  they  became  self-supporting. 
He  noted  that  the  tremor  decreased,  excitement  diminished,  there  was 
an  improvement  in  memory  and  in  mental  agility.  The  longest  period 
of  remission  initiated  by  the  therapy  was  3  years. 

In  a  second  series  of  15,  9  showed  definite  improvement,  of  whom 
3  were  able  to  again  become  self-supporting. 

Hauber  gave  a  combined  antiluetic  and  nonspecific  treatment  to 
36  patients.  Of  these  13  improved,  but  23  showed  no  evidence  of 
therapeutic  effect. 

Szedlak  treated  25  patients  simply  with  the  nucleic  acid  and  an 
equal  number  with  nucleic  acid  and  mercury  with  the  following  re- 
sults: 

Nuc.  alone.  Nuc.  and  Hg. 

Marked  improvement 8%  40% 

Slight  improvement  24%  24% 

No  improvement 31%  16% 

Interrupted  treatment   4%  4% 

Died  33%  16% 

In  a  more  recent  paper  V.  Jauregg  reported  the  treatment  of  33 
cases  with  staphylococcus  vaccine  in  lieu  of  tuberculin  formerly  used. 
In  this  series  61%  improved,  10  of  the  patients  being  restored  to 
almost  normal  health,  v.  Economo  reported  similar  results.  Schacherl 
treated  38  cases  of  general  paralysis  (ambulatory)  with  a  combined 
course  of  tuberculin  and  mercury.  Of  these  13  continued  the  course 
to  completion.  Seven  of  these  were  much  improved,  5  of  them  were 
again  enabled  to  earn  their  living.  One  developed  a  phlegmon  after  a 
severe  eczema;  this  patient  became  lucid  and  was  permanently  cured. 

Of  course  these  favorable  results  have  not  been  allowed  to  stand 
unchallenged.  Hiissels,  Lepine,  Jolowicz,  Plange  and  Hoppe  failed  to 
find  any  therapeutic  benefit  from  the  use  of  tuberculin  or  the  nucleins 
when  injected.  Lowenstein  and  Kleinberger  have  indeed  claimed  that 
the  injections  have  done  actual  harm.  Bouman,  who  used  tuberculin, 


TREATMENT  OF  GENERAL  PARALYSIS,  TABES,  ETC.    227 

nucleinate  and  salvarsan,  got  very  little  results  with  any  of  them, 
the  effect  obtained  being  at  the  most  transient. 

Brown  and  Ross  have  discussed  this  treatment  of  mental  dis- 
eases by  the  production  of  leukocytosis,  treating  9  cases  by  means  of 
nuclein  injections.  There  was  not  much  mental  improvement  despite 
the  fact  that  a  leukocytosis  of  from  17,000  to  20,000  was  obtained  in 
many  cases. 

Bruce  has  reported  on  the  use  of  turpentine  and  sodium  cinnamate, 
and  collargol  has  also  been  tried  by  Vergueira  in  a  dose  of  from  5 
to  10  c.c.  of  a  1%  solution. 

Friedlander  has  used  intravenous  typhoid  injections;  Plaut  tried 
out  the  effect  of  injections  of  streptococcus  and  of  staphylococcus  vac- 
cines without  apparent  results;  the  leukocytic  response  was  of  low 
grade.  Recently  v.  Jauregg  has  even  suggested  the  infection  of  the 
patient  with  malaria  plasmodia  to  keep  up  a  febrile  reaction  at 
definite  intervals.  Weichbrodt  and  Jahnel  report  on  a  number  of  cases 
so  treated  and  Miihlens,  Weygandt,  and  Kirschbaum  have  recently 
reported  on  a  series  of  33  cases  treated  by  infecting  the  patients 
with  the  spirillum  of  Obermeier  and  malaria  plasmodia.  Of  their  series 
12  were  of  such  recent  date  that  the  end  result  could  not  be  properly 
judged.  Of  the  remaining  21,  4  cases  died  (not  directly  from  the 
infection) ,  while  12  were  markedly  improved,  with  remissions  persist- 
ing for  a  considerable  time.  The  papers  by  Steiner  and  Pagniez  are 
also  of  interest  in  the  same  connection.  A  review  of  the  entire  sub- 
ject will  be  found  in  articles  by  Enge  and  by  Raecke. 

We  are  perhaps  justified  in  assuming  that  the  work  of  the  Vienna 
school  in  this  particular  field  may  offer  some  advance  in  our  methods 
of  therapy  which,  at  best,  are  none  too  satisfactory.  That  intercur- 
rent  infections  affect  the  degenerative  process  or  at  least  the  rate 
of  destruction  is  very  likely  from  what  we  know  of  their  effect  on 
other  pathological  conditions,  and  there  is  no  reason  why  the  various 
nonspecific  procedures  suggested  may  not  at  times  be  followed  by 
some  clinical  improvement.  It  seems  possible  that  in  a  combined 
ergotropic  and  etiotropic  method  some  dependable  results  may  yet 
be  achieved. 

TABES 

Dollken  has  treated  some  cases  of  tabes,  but  a  larger  series  has 
been  reported  by  Schacherl.  Schacherl  used  a  combined  specific  and 
nonspecific  method  of  therapy,  beginning  with  0.001  gr.  of  tuberculin 
and  then  giving  0.1  gm.  of  salicylate  of  mercury  with  each  third  dose 
of  tuberculin.  He  observed  that  early  in  the  course  of  treatment, 
i.e.,  when  the  patient  had  considerable  reaction  from  the  tuberculin,  the 
effect  of  the  mercury  was  also  much  more  in  evidence,  salivation  being 
noted  much  more  frequently. 

With  this  method  of  treatment  the  results  in  76  cases,  with  one 


228  PROTEIN  THERAPY 

exception,  were  very  good.  At  times  an  initial  intensification  of  the 
disease  symptoms  was  observed  with  the  beginning  of  the  treatment, 
but  later  this  subsided.  While  the  ataxia  was  not  much  altered,  an 
increase  in  the  rapidity  of  transmission  of  sensory  stimuli  was  ap- 
parent in  all  cases  and  the  ability  of  the  patient  to  work  was  greatly 
enhanced. 

An  analysis  of  the  results  of  treatment  of  the  76  cases  follows: 

53  were  of  the  ataxic  type — 36  were  much  improved,  17  were 
slightly  improved  in  walking. 

46  suffered  from  lancinating  pains — 38  of  these  were  cured,  5  were 
improved. 

24  gastric  crises — of  these  23  were  cured. 

25  had  bladder  symptoms — 12  were  cured,  11  improved. 

Miller  is  said  to  have  observed  that  the  lancinating  pain  disap- 
peared after  milk  injections  (Boas).  Wodak  treated  a  number  of 
tabetics  with  tuberculin  and  found  that  the  patellar  reflex  was  re- 
stored in  several  of  his  patients  after  the  treatment.  Friedlander  is 
said  to  have  obtained  a  similar  result. 

It  is  to  be  remembered  in  this  connection  that  while  we  may 
at  times  improve  the  symptoms  existing  in  the  tabetic,  at  other  times 
a  nonspecific  injection  may  precipitate  a  gastric  crisis  or  lancinating 
pains.  Schmidt  indeed  calls  attention  to  this  possibility  as  a  mani- 
festation of  the  focal  activation  so  frequently  observed  following  non- 
specific injections. 

Itten  tried  nonspecific  therapy  in  the  treatment  of  dementia  prcecox, 
treating  a  series  of  9  cases  with  injections  of  a  2%  solution  of  rmclein 
(giving  from  0.5  to  1.4  gm.).  The  cases  were  not  improved.  Dollken 
has  treated  21  cases  of  whom  16  temporarily  improved  following  in- 
jections of  pyocyaneus  and  dysentery  vaccines. 

EPILEPSY 

A  number  of  procedures,  essentially  nonspecific  in  character,  have 
been  tried  in  the  treatment  of  epilepsy,  beginning  with  the  use  of 
serum  injections  by  Ceni  in  1903,  brain  extract  by  Lion  in  1911, 
cerebrospinal  fluid  by  Gordon  in  1914  and  immune  rabbit  serum 
by  Held.  Turner  treated  23  cases  with  colloidal  platinum  injections 
and  noted  a  diminution  in  the  number  and  intensity  of  the  attacks. 

More  recently  two  interesting  reports  have  been  published  by 
Dollken  and  by  Edgeworth. 

Dollken  used  a  combined  milk  and  luminal  therapy;  to  the  milk 
injections  he  added  a  small  amount  of  vaccine  (nonvirulent  organisms) 
and  injections  were  usually  given  twice  a  week;  after  therapeutic 
improvement  took  place  the  number  of  injections  were  decreased. 


TREATMENT  OF  GENERAL  PARALYSIS,  TABES,  ETC.     229 

Twelve  cases  were  free  from  attacks  for  a  period  of  18  months,  60  for 
one  year.  As  a  rule  from  4  to  6  months  were  required  for  treatment. 
In  13  cases  the  result  was  not  a  complete  cure,  but  merely  an  improve- 
ment. 

Edgeworth's  series  was  smaller  and  the  course  of  treatment  shorter. 

In  the  series  of  twenty-three  cases  a  5  per  cent,  solution  of  pep- 
tone was  used,  made  up  according  to  the  prescription  of  Auld.  It 
was  injected.  If  a  fortnight  went  by  without  the  occurrence  of  an  at- 
was  5  minims.  In  succeeding  weeks  7,  10,  15  and  20  minims  were 
given  unless  toxic  symptoms  occurred.  No  dose  greater  than  20  minims 
was  injected.  If  a  fortnight  went  by  without  the  occurrence  of  an  at- 
tack, the  dose  was  not  further  increased.  If  no  results  were  obtained 
after  three  doses  of  20  minims  the  treatment  was  given  up.  In  four  cases 
toxic  symptoms  were  observed,  rigor,  vomiting,  temporary  pyrexia, 
either  as  an  isolated  phenomenon,  or  in  any  combination.  If  this 
happened,  the  next  dose  was  lessened.  In  such  cases  it  was  found 
that  the  dose  could  be  increased  later  to  the  old  figure  or  even  beyond 
without  the  occurrence  of  any  untoward  symptoms.  In  three  cases 
of  posthemiplegic  epilepsy  no  improvement  occurred.  In  eleven  cases 
of  epilepsy  without  signs  of  any  gross  cerebral  lesion  no  permanent 
arrest  was  produced.  In  four  of  these  the  fits  ceased  but  subsequently 
recurred,  though  in  lessened  severity,  and  in  two  cases  the  frequency 
was  lessened.  The  average  age  of  the  patients  was  18  years,  the 
average  duration  of  the  disease  ten  years,  and  the  average  frequency 
of  attacks,,  once  a*week.  In  nine  cases  of  epilepsy  without  physical  signs 
of  any  gross  cerebral  lesion  the  attacks  ceased.  This  arrest  has  now 
lasted  more  than  a  month  in  all  cases,  and  in.  some  as  long  as  three 
months.  Five  of  the  patients  were  mentally  defective — in  one  of  these 
cases  no  mental  improvement  occurred,  in  three  some  improvement, 
and  in  one  considerable  improvement  was  noted.  The  average  number 
of  injections  given  was  five  and  one-half. 

Geyelin  has  recently  reported  that  fasting  may  at  times  be  followed 
by  the  cure  of  epilepsy.  Whether  the  therapeutic  effect  is  dependent 
on  the  acidosis  involved  in  the  method,  and  thereby  related  to  other 
nonspecific  shock  effects,  has  not  been  established. 


CHAPTER  XV 
SKIN  DISEASES 

"To  treat  skin  disease  wholly  from  without,"  Ravaut  has  recently 
declared,  "is  as  irrational  as  treating  the  skin  lesions  of  syphilis  by 
local  applications  alone.  And  yet  the  dermatologist  is  too  apt  to 
focus  his  attention  exclusively  on  the  local  process.  He  must  be  a 
biologist,  not  a  mere  botanist."  While  Ravaut's  statement  is  rather 
broad,  there  is  nevertheless  much  value  in  the  emphasis  that  he  places 
on  the  fact  that  the  dermatologist,  as  the  result  of  more  recent  work 
in  the  general  pathology  and  physiology  of  the  skin,  must  not  be 
satisfied  with  a  purely  local  conception  of  the  pathology  or  the  therapy 
of  the  particular  disease  that  may  be  under  consideration. 

Not  only  must  we  consider  the  fact  that  general  systemic  re- 
actions can  profoundly  alter  the  reactivity  of  the  skin — both  en- 
hancing or  retarding  inflammatory  processes — but  we  must  take  cog- 
nizance of  the  fact  that  the  integument  seems  to  respond  to  bacterial 
invasion  or  protein  injection,  perhaps  even  to  other  chemical  or  physi- 
cal agents  with  an  allergy,  an  alteration  in  reactivity  which  is  the 
more  remarkable  in  that  it  seems  to  be  a  definitely  localized  phe- 
nomenon, an  acquired  property  of  the  individual  cell.  This  allergy, 
once  established,  may  be  transplanted  if  the  cell  is  transplanted,  but 
the  general  organism  need  take  no  part  in  the  alteration  whatso- 
ever. 

Equally  interesting  is  the  effect  of  the  stimulation  of  skin  metab- 
olism and  the  effect  on  systemic  diseases,  as  Heims  has  indicated  and 
as  Bloch  and  Hoffman  have  discussed  at  greater  length.  These  have, 
however,  been  discussed  in  another  chapter. 

During  the  past  two  decades  a  considerable  number  of  observa- 
tions concerning  the  effects  of  systemic  alterations  on  skin  diseases 
have  been  gathered,  but  even  previously  one  finds  isolated  records 
that  are  of  particular  interest.  One  needs  but  recall  the  observation 
that  a  variety  of  drugs — thyophen,  benzol,  acetone,  taurin  and  amines 
(Spiegler),  atoxyl  (Moro  and  Stheeman),  cantharidic  acids  and  salts 
(Liebreich) — would,  when  injected,  cause  a  reaction  at  a  lupus  focus; 
that  dietary  faults  aggravate  an  eczema;  that  intercurrent  infections 
would  favorably  influence  a  preexisting  skin  lesion  (Restrepo  has  but 
recently  reported  such  a  case)  or  that  yeast  therapy  might  influence 
a  furunculosis. 

Skin  diseases  have  afforded  particularly  favorable  material  for 

230 


SKIN  DISEASES  231 

treatment  by  vaccines,  and  the  treatment  of  acne  and  of  furunculosis 
became  more  or  less  the  special  field  of  the  vaccinotherapist.  Sero- 
logical  procedures,  too,  such  as  that  of  autoserotherapy  in  psoriasis, 
have  had  their  advocates.  The  fact  that  the  results  could  be  judged 
quite  objectively  has  made  this  field  one  of  interest  and  value. 

Linser  in  working  with  the  dermatoses  of  pregnancy  found  that 
the  injection  of  serum  (normal)  was  at  times  followed  by  marked 
improvement  and  the  application  was  extended  to  urticaria,  purpuras, 
strophulus,  pruritus  and  related  conditions  where  vascular  altera- 
tions might  be  surmised  as  the  basis  of  the  pathology.  Zieler,  Bingel, 
Henck,  Lowenberg  and  others  have  reported  results  that  were  con- 
firmatory. Later  psoriasis  came  to  be  selected  for  treatment  of  this 
kind  and  a  number  of  American  observers  have  reported  their  ob- 
servations with  this  method  of  therapy.  (Lit.  by  Luithlen.) 

Quite  a  number  of  nonspecific  procedures  have  been  applied  in 
the  therapeutics  of  skin  diseases  in  recent  years.  The  use  of  au- 
togenous serum  injections  in  psoriasis  was  occasionally  followed  by  a 
degree  of  improvement,  although  the  method  was  too  cumbersome  to 
come  into  popular  use.  Perry,  however,  substituted  normal  horse 
serum  for  autogenous  serum  with  satisfactory  results.  From  6  to  9 
injections  were  necessary  to  produce  therapeutic  effects. 

Milk  injections  were  used  shortly  after  their  introduction  by 
Schmidt  and  others.  That  tuberculin  would  cause  the  secondary 
lesions  of  syphilis  to  undergo  involution  was  reported  by  Blach,  while 
Scholz  has  discussed  the  fact  that  tuberculosis  of  the  skin  reacts  to 
injections  of  trichophytin  as  well  as  to  a  variety  of  other  substances. 
Engmann  and  McGarry  began  the  use  of  typhoid  vaccine  in  the 
treatment  of  a  variety  of  skin  diseases,  among  them  a  few  syphilids, 
exfoliative  dermatitis,  lupus  erythematosis  and  psoriasis.  Engmann 
and  McGarry  made  use  of  typhoid  vaccine  in  dosage  of  from  75  to 
500  million. 

Scully  in  1917  reported  on  the  treatment  of  several  cases  of 
psoriasis  with  injections  of  typhoid  vaccine,  8  cases  being  treated  with 
injections  varying  from  75  to  100  million  organisms.  The  results  were 
not  very  satisfactory;  Scully  noted  that  the  effect  of  the  injections 
on  the  temperature  and  leukocyte  curve  was  not  as  marked  in  these 
skin  cases  as  it  had  been  in  the  cases  of  arthritis  treated  by  him. 
Rezende's  reports  show  the  prompt  and  radical  cure  of  extensive 
psoriasis  under  "protein  shock"  treatment.  It  was  in  the  form  of  20 
c.c.  of  normal  horse  serum,  injected  into  the  abdominal  wall.  An 
injection  of  10  c.c.  two  days  before  had  not  induced  an  appreciable 
reaction,  but  the  20  c.c.  caused  fever  for  five  days,  reaching  39.6°  C. 
(103.5°  F.)  the  third  day.  By  the  eighth  or  tenth  day  the  eruption 
had  practically  subsided. 

These  observers  used  rather  severe  reactions;  it  is  possible  that 
more  satisfactory  results  would  be  obtained  when,  with  smaller  doses, 


232  PROTEIN  THERAPY 

less  severe  reactions  could  be  used  over  a  longer  period  of  time,  as 
suggested  by  Van  Alstyne. 

More  recently  Klingmueller  has  reintroduced  the  injection  of 
turpentine  as  a  method  of  treatment  of  skin  diseases.  Turpentine 
has,  as  it  will  be  recalled  in  connection  with  the  work  of  the  "Fixa- 
tion abscess,"  been  used  before  in  therapy  as  a  subcutaneous  injec- 
tion. Klingmueller,  however,  has  modified  the  procedure  so  that  quite 
minute  amounts  are  injected  over  a  long  period  of  time.  By  this 
method  20%  turpentine  is  dissolved  in  olive  oil  and  injections  of 
about  4  drops  (0.01  turpentine)  are  made  at  3-day  intervals.  Karc 
and  others  have  improved  the  method  by  adding  a  minute  amount 
of  eukupin  or  novocain  to  the  oil  mixture  in  order  to  prevent  any 
discomfort  to  the  patient. 

Klingmueller  found  that  the  injections  were  followed  by  favorable 
effects  not  only  in  trichophyton  infections,  but  in  acne,  acute  derma- 
titis, eczema,  salvarsan  dermatitis  and  strophulus  as  well.  In  lupus 
vulgaris  and  in  tuberculous  glands  he  observed  typical  focal  reactions. 
There  was  no  evidence  of  kidney  irritation  following  the  injections. 

A  number  of  observers  have  worked  with  this  method.  Thus 
Holzhauser  and  Werner  reported  excellent  results  in  the  treatment 
of  leg  ulcers  and  impetiginous  skin  conditions.  Appel,  too,  has  tried 
it  in  a  series  of  cases.  In  all  the  staphylococcic  infections  (furuncu- 
losis,  acne-like  eruptions  and  pyodermia,  in  moist  eczema,  in  pruritus 
universalis, — both  essential  and  symptomatic — and  in  urticaria)  Appel 
reports  quite  remarkable  improvement  in  most  cases.  Lupus  reacted 
to  the  injections  just  as  it  does  to  tuberculin.  In  the  deeper  nodules 
of  trichophyton  infection  a  gradual  lessening  of  the  infiltration  and 
size  of  the  foci  was  noted.  Gewalt  reports  the  treatment  of  pemphigus 
by  the  same  method. 

Lowenfeld  and  Paulay  have  made  a  very  careful  study  of  tri- 
chophyton infection,  treating  cases  with  three  different  methods,  one 
series  on  a  strictly  specific  basis  with  trichon,  an  autolytic  product*  of 
the  infecting  organism;  one  series  with  a  nonspecific  protein — tuber- 
culin; the  other  with  a  nonspecific  chemical  agent — turpentine,  recog- 
nizing, of  course,  that  when  injecting  the  turpentine  it  represented  a 
form  of  protein  therapy,  in  this  case  homologous  protein  from  the 
inflammatory  focus  produced  by  the  turpentine.  There  was  little  or 
no  difference  in  the  therapeutic  end  result  whether  the  specific  or 
nonspecific  methods  were  used.  The  deeper  nodular  infiltrations  were 
gradually  absorbed  under  the  course  of  the  injections,  the  more  super- 
ficial lesions  showed  less  improvement.  Lowenfeld  and  Paulay  sug- 
gest that  this  result  is  to  be  expected  in  that  the  more  superficial 
lesions,  like  those  of  favus,  microsporia,  pityriasis  versicolor,  ery- 
thrasma,  etc.,  are  much  less  susceptible  to  the  general  metabolic 
change  that  is  brought  about  either  by  specific  or  nonspecific  therapy. 

Fischl  treated  50  cases  of  trichophyton  infection  with  turpentine 


SKIN  DISEASES  233 

injections  and  resorcin,  using  resorcin  as  a  local  application  and  giving 
turpentine  injections  every  two  days.  He  commenced  with  a  dose  of 
0.25  c.c.  of  the  20%  turpentine  in  olive  oil,  advanced  to  0.5  c.c., 
then  followed  to  0.75  and  1  c.c.  doses  during  the  course  of  the  treat- 
ment. He  found  the  treatment  of  great  value  in  the  deep  indura- 
tive  forms;  in  these,  injections  of  trichophytin  were  also  found  use- 
ful. The  cases  were  cured  as  a  rule  in  about  3  weeks ;  the  fungus  dis- 
appeared from  the  lesions  generally  during  the  course  of  the  first 
week.  In  four  cases  (of  30)  there  was  some  temperature  reaction 
after  the  injections,  one  of  these  cases  reaching  39.6°  C.,  but  Fischl 
does  not  consider  the  clinical  effect  in  any  way  depending  on  the 
degree  of  temperature  rise. 

Miiller  used  turpentine  diluted  with  paraffin  oil  in  the  treatment 
of  trichophyton  infections  with  satisfactory  results.  He  used  no  local 
treatment.  There  was  no  evidence  of  kidney  irritation  following  the 
injections.  Grabisch  began  the  use  of  turpentine  injections  in  the 
same  condition  and  gradually  extended  his  use  of  the  injections  to 
acute  eczema,  dermatitis,  drug  eruptions,  gonorrheal  complications, 
urticaria,  strophulus,  erythema  multiforme,  dermatitis  herpetiformis, 
furunculosis,  pyodermia,  etc. 

Ruete,  on  the  other  hand,  found  that  turpentine  injections  were 
not  followed  by  particularly  favorable  results  in  trichophyton  infection 
although  he  obtained  very  satisfactory  results  in  furunculosis. 
Schmidt  (H.  E.)  reached  the  same  conclusion.  Using  Klingmueller's 
method  he  treated  8  superficial  cases  and  6  with  deep  seated  lesions. 
In  the  latter  cases  the  results  were  far  better  than  in  the  superficial 
ones,  but  even  these  were  not  cured.  In  5  cases  of  furunculosis  his 
results  were  very  satisfactory.  Schedler's  results  were  more  satis- 
factory. 

Sachs  recommends  intravenous  injections  of  hexamethylenamin 
(40%  sol.)  in  the  treatment  of  deep  trichophyton  infection,  with  large 
nodules.  As  a  first  dose  6  gm.  (15  cm.  of  fluid)  are  injected;  on  the 
second  or  third  day  after  the  first  injection  the  dose  is  increased  to 
8  gm.  In  one  case  8  gm.  were  given  as  a  first  dose,  which  was  in- 
creased to  12  and  14  gm.  The  number  of  injections  required  and 
the  exact  quantities  of  hexamethylenamin  that  will  be  needed  cannot 
be  definitely  stated  in  advance.  Of  ten  patients  so  treated,  one  was 
cured  after  a  single  injection  of  4  gm.,  another  after  three  injections 
of  4,  6  and  8  gm.,  respectively,  in  ten  days;  another  patient  received 
four  injections  (once  6  gm.  and  three  times  8  gm.),  and  was  cured 
in  fourteen  days. 

Singermann  found  turpentine  injections  (10%)  useful  in  furun- 
culosis and  in  eczema,  and  Becker  reports  success  in  the  treatment  of 
various  dermatoses. 

Reese  used  milk  injections  (aolan)  in  175  cases  of  trichophyton 
infection.  He  found  that  the  cases  were  as  a  rule  cured  in  about  three 


234  PROTEIN  THERAPY 

weeks,  the  number  of  injections  averaging  about  3.  Scholz  and  Kraus 
and  Miiller  also  report  favorable  results  from  milk  and  aolan  injec- 
tions. Loeb  used  "leukogen,"  a  staphylococcus  vaccine  of  which  large 
doses  are  injected,  with  success.  Antoni  found  "aolan"  satisfactory  in 
trichophyton  infection.  Sellei,  in  comparing  the  value  of  milk  and 
turpentine  injections,  found  that  the  milk  effect  was  more  sustained 
and  continuous.  He  obtained  very  satisfactory  results  in  universal 
pruritus,  and  in  superficial  skin  suppurations;  in  the  deeper  lesions  the 
effect  was  less  apparent.  In  eczema  he  obtained  no  results. 

The  work  of  Engmann  and  McGarry,  of  Scully  and  of  Van  Alstyne 
in  the  treatment  of  psoriasis  has  already  been  mentioned.  Cemach  has 
used  tuberculomucin  in  one  case  with  favorable  results,  while  Konte- 
schweller  calls  attention  to  the  fact  that  all  colloidal  injections,  just 
as  vaccines  and  heterovaccines,  act  on  the  general  system  of  the 
patient  and  improve  his  physical  condition  and  in  so  far  are  useful 
in  the  treatment  of  psoriasis.  It  is  just  this  fact  that  Sabouraud 
emphasizes.  He  considers  that  the  treatment  of  psoriasis  has  entered 
on  a  new  era  of  late  with  the  discovery  that  certain  measures  which 
have  nothing  in  common,  except  that  they  all  give  a  kind  of 
shake-up  to  the  organism,  are  proving  effectual  in  certain  cases, 
although  not  in  all.  The  list  includes  injection  of  mercurial  salts, 
of  antitoxic  serums,  and  of  emulsions  of  killed  microbes  from  the 
patient's  stools.  He  hopes  that  still  more  effecutal  means  of  induc- 
ing the  shake-up  or  shock  may  yet  be  found.  The  field  of  experi- 
mentation seems  immense  and  almost  unlimited.  Sabouraud  finds 
Danysz'  enterovaccine  from  the  stools  to  be  harmless,  and  great 
improvement  under  it  seems  to  occur  in  more  cases  and  to  last  longer 
than  with  any  other  measures  yet  known. 

In  five  cases  that  Cadbury  treated  with  typhoid  vaccine  excellent 
temporary  results  were  obtained  but  they  all  relapsed  sooner  or  later. 

Just  as  furunculosis  has  been  very  satisfactorily  treated  with  vac- 
cines of  all  kinds,  so  other  and  less  specific  methods  of  treatment 
have  been  followed  by  considerable  clinical  success.  Kaiser  claims 
results  following  the  injection  of  "tebelon"  (the  isobutyl  ester  of  oleic 
acid),  Schedler  used  turpentine  injections,  Morris  and  Levinson  col- 
loidal metals,  and  milk  injections  have  also  found  extensive  employ- 
ment. 

The  eczemas,  both  the  dry  and  exudative  types,  have  been  more 
or  less  resistant  to  nonspecific  therapy.  Spurgin  tried  salt  infusion 
without  apparent  effects,  while  Cadbury  treated  4  cases  with  typhoid 
vaccine  and  observed  practically  no  improvement. 

A  number  of  other  skin  lesions  have  given  more  promise  of  suc- 
cess. Schrameck  reports  a  case  of  pemphigus  treated  successfully; 
Cadbury  treated  two  cases  of  lichen  planus  with  typhoid  vaccine  which 
improved  and  one  case  of  erythema  nodosum  which  was  cured  after 
two  injections.  Hebermann  was  successful  in  the  treatment  of  hys- 


SKIN  DISEASES  235 

teric  dermatoses.  In  lichen  rubra  Spitzer  found  that  he  obtained 
successful  therapeutic  effects  with  salvarsan  injections  provided  that 
a  typical  Herxheimer  reaction  followed  the  injection,  i.e.,  the  salvarsan 
acted  as  a  nonspecific  agent  in  bringing  about  plasmaactivation. 

Ziembowski  is  so  far  the  only  one  who  has  reported  cases  of 
actinomycosis  treated  with  nonspecific  injections.  He  used  milk  in 
three  cases  with  excellent  results. 

Kingsbury  and  Bechet  have  but  recently  called  attention  to  the 
favorable  influence  of  blood-letting  on  certain  dermatoses.  Veni- 
puncture,  according  to  the  researches  of  Luithlen,  represents  a  non- 
specific method  closely  allied  to  the  other  and  more  mild  methods  of 
treatment  which  have  their  chief  effect  in  alterations  in  the  permeabil- 
ity of  the  capillaries.  Achard  and  Flandin  make  use  of  the  same 
phenomenon.  They  state  that  in  conditions  in  which  the  factor  of 
anaphylaxis  is  evident,  the  serum  acquires  what  they  call  cryptotoxic 
properties,  and  can  be  utilized  to  desensitize.  They  give  it  in  minute 
doses  below  the  level  of  those  inducing  shock  or  even  the  hemoclastic 
crisis,  injecting  subcutaneously  0.5  c.c.  of  the  autoserum;  twelve 
hours  later,  1  c.c.  and  the  next  day  1  or  2  c.c. ;  2  c.c.  the  following  day, 
and  then  every  second  or  third  day.  Recurring  urticaria,  angioneuro- 
tic  edema  and  hay-fever  yielded  promptly  to  this  treatment,  but  lit- 
tle effect  was  apparent  in  asthma.  Their  experience  with  hay-fever 
has  been  limited,  but  one  case  cured  in  1918  had  only  very  slight 
symptoms  the  following  year.  The  effect  of  this  treatment  is  not 
like  that  of  ordinary  serotherapy  but  seems  to  be  an  actual  desensi- 
tization. 


CHAPTER  XVI 
DISEASES  OF  THE  EYE 

Isolated  instances  of  successful  vaccinotherapy  when  large  doses  of 
organisms  were  employed  in  certain  cases  of  eye  diseases  have  been 
reported  during  the  past  ten  years  or  more,  as  for  instance  by  Grey, 
Gorbunow,  Bryan  and  by  Allen.  Romer  treated  hypopyon  keratitis 
with  large  doses  of  vaccine  and  also  used  autoserothcrapy  with  some 
success,  using  the  patients'  serum  drawn  from  a  blister.  A  large 
number  of  other  observers,  Darier,  W.  Zimmermann,  Fromaget  among 
them,  successfully  used  diphtheria  antitoxin  injections,  v.  Szily  used 
huge  doses  of  gonococcus  vaccine  (arthogon)  in  the  abortive  treatment 
of  ophthalmoblennorrhea  with  surprisingly  good  results,  but  it  was 
not  until  the  report  of  Miiller  and  Thanner  was  published  that  much 
attention  was  given  to  therapy  of  this  nature.  In  fact,  the  use  of 
nonspecific  therapy  in  the  treatment  of  eye  diseases  may  be  stated 
to  date  from  their  observations. 

Miiller  and  Thanner  injected  5  c.c.  of  milk  intramuscularly  in 
4  cases  of  parenchymatous  keratitis,  all  of  whom  improved,  as  did 
likewise  11  cases  of  iritis.  It  was  noted  that  when  the  iritis  was  due 
to  gonococcus  infection  the  improvement  was  not  as  prompt  as  in 
those  of  rheumatic  origin  or  iritides  of  undetermined  etiology.  In 
these  the  pain  and  photophobia  disappeared  in  24  hours.  In  nine  cases 
of  corneal  opacity  (without  choroiditis)  little  improvement  was  ob^ 
served,  nor  did  they  see  any  effect  on  choroiditis. 

Friedlander  began  the  treatment  of  trachoma,  using  a  somewhat 
larger  dosage  (10  c.c.  of  milk  intramuscularly  injected).  In  42  cases 
so  treated  the  results  were  reported  to  be  excellent.  Injections  were 
given  every  4  days. 

Hiihn  had  noted  previously  that  trachoma  cases  under  his  care 
in  a  hospital  for  children  improved  remarkably  during  the  course  of 
a  scarlet  fever  epidemic  and  then  tried  out  the  use  of  milk  injections, 
too,  in  order  to  simulate  the  clinical  picture  of  the  spontaneous  disease. 
He  reports  that  with  the  milk  he  obtained  excellent  results.  Rosen- 
stein  treated  trachoma  with  milk  injections  with  satisfactory  results; 
Konigstein,  in  a  discussion  at  the  Gesellschaft  fur  Aerzte  at  Vienna, 
stated  that  in  some  thirty  cases  he  had  witnessed  both  increased  ir- 
ritation and  also  improvement  in  his  cases.  Blatt  does  not  believe 
that  the  method  is  useful.  Pflugk,  also  using  milk,  obtained  good 
results  in  iritis,  in  keratitis  parenchymatosa  and  in  adult  blennorrhea. 

236 


DISEASES  OF  THE  EYE  237 

Heinemann  and  Wilke  report  excellent  results  with  milk  injections  in 
adult  blennorrhea  and  severe  eye  infections. 

Three  rather  extensive  reports  have  recently  been  published,  those 
of  Possek,  of  Berneaud  and  of  Jendralski.  Possek  (as  well  as  Haab) 
used  a  typhoid  vaccine,  killed  with  phenol  and  made  up  with  approxi- 
mately 500  million  organisms  to  the  cubic  centimeter.  Of  this  he 
injected  from  0.6  to  1  c.c.  subcutaneously  the  first  day  and  1  c.c.  the 
second  day.  Following  these  injections  there  was  usually  a  tempera- 
ture reaction  of  mild  degree. 

This  vaccine  therapy  was  applied  to  a  series  of  eye  conditions 
of  undoubted  luetic  origin,  52  of  which  were  of  long  standing,  32  of 
which  were  recent.  Of  the  old  cases  16  were  congenital  lues,  the 
balance  acquired.  These  cases  had  had  mercury  and  salvarsan  treat- 
ment for  a  long  time  before  they  were  treated  with  vaccine,  but  with- 
out apparent  benefit.  Possek  selected  the  cases  that  had  not  re- 
sponded to  the  specific  therapy  for  his  experiments  with  vaccines. 
In  a  few  cases  where  no  luetic  basis  was  at  first  suspected  and  non- 
specific treatment  given  without  previous  specific  therapy,  excellent 
results  were  obtained,  although  later  the  luetic  nature  of  the  trouble 
was  established  serologically.  Among  these  cases,  4  of  hereditary 
keratitis  were  markedly  benefited,  the  inflammation  of  the  iris  re- 
ceded and  the  cornea  cleared  up.  In  several  cases  of  retinal  hemor- 
rhage the  hemorrhage  was  resorbed,  and  in  cases  of  turbidity  of  the 
lens,  a  definite  clearing  was  observed.  Good  results  were  obtained, 
too,  with  optic  neuritis. 

A  large  series  of  cases  (500)  have  been  reported  by  Berneaud. 
Berneaud  gave  over  2,000  injections  of  milk  to  these  patients  and  his 
results  are  of  considerable  interest.  He  obtained  little  or  no  result 
in  the  treatment  of  glaucoma,  amotio  retina?,  lacrymal  duct  inflam- 
mation, neuritis,  neuroretinitis,  multiple  sclerosis,  in  keratitis  paren- 
chymatosa  or  ophthalmoblennorrhea. 

On  the  other  hand,  in  keratitis  eczematosa  and  scrofulosa,  and  in 
secondary  glaucoma  following  iritis  marked  improvement  was  noted. 
In  70  cases  of  iritis  60  were  cured  or  markedly  improved  after  the 
injection.  In  24  cases  of  choroiditis  6  were  much  improved,  10  partly 
improved  and  8  not  altered.  In  his  trachoma  cases  he  found  that  the 
corneal  ulceration  was  improved  while  the  connective  tissue  inflamma- 
tion of  the  conjunctiva  was  not  much  influenced.  Of  11  cases  of 
gonorrheal  conjunctivitis  9  responded  very  well.  On  a  concomitant 
vulvovaginitis  in  some  of  these  cases  there  was  no  apparent  effect. 
Herpes  of  the  cornea  was  also  favorably  influenced. 

Jendralski  treated  100  cases  of  eye  disease  with  milk  injections. 
In  phlyctenular  disease  some  improvement  was  observed,  more  often 
in  the  subjective  direction  than  in  objective  alteration.  Trachoma 
was  not  altered  and  in  corneal  ulceration  Jendralski  urges  great  caution 
lest  actual  pref oration  may  follow.  In  iritis  the  results  were  excellent; 


238  PROTEIN  THERAPY 

several  cases  of  ophthalmoblennorrhea  improved  rapidly.  In  tuber- 
culous iridocylitis  the  improvement  was  not  marked. 

Both  Igersheimer  and  Kraupa  obtained  remarkable  results  in  iritis 
and  found  that  in  gonorrheal  disease  the  results  were  usually  very 
satisfactory  both  in  adults  and  in  children. 

Jacovides  treated  about  221  cases  of  ocular  disease  with  nonspecific 
therapy.  In  150  cases  of  ulcer  of  the  cornea  140  were  cured  after  2 
to  3  injections. 

Jickeli,  using  milk,  treated  ophthalmoblennorrhea,  iritis,  choroiditis 
and  ulcers  of  the  cornea  with  satisfactory  results;  milk  therapy  has 
found  many  partisans  among  French  and  Latin  clinicians,  and  the 
reports  of  Carreras,  Darier,  Dimmer,  Miiller,  Domec,  Mansilla, 
Arganaraz,  Gaupillat,  Guibert  are  available,  while  Titus  and  Nolf 
have  used  intravenous  injections  of  peptone.  Nolf  has  paid  particular 
attention  to  this  form  of  therapy  in  ocular  complications  following 
typhus,  typhoid  and  septicemia.  Guibert  obtained  his  most  satis- 
factory results  in  scrofulous  diseases.  Gaupillat  obtained  very  satis- 
factory results  in  hypopyon  keratitis  and  in  bulbous  infection.  He 
used  milk  injections  for  subconjunctival  injection  in  one  case. 

Darier,  one  of  the  earliest  advocates  of  paraspecific  therapy,  used 
milk  injections  together  with  oral  administration  of  serum,  which,  as 
Cumston  has  recently  mentioned,  is  so  frequently  used  as  a  routine 
by  French  clinicians.  Darier's  results  in  infectious  ulcers  of  the 
cornea  and  in  iritis — traumatic  as  well  as  postoperative — were  very 
satisfactory.  In  keratitis  parenchymatosa  and  in  trachoma  he  does 
not  consider  his  results  conclusive. 

Darier  has  been  indefatigable  in  his  advocacy  of  the  oral  ad- 
ministration of  serum,  claiming  that  with  little  reaction  on  the  part 
of  the  patient  the  polyvalent  serum  exerts  a  systemic  stimulation  com- 
parable to  the  effect  of  milk,  peptone  or  colloidal  metals  injected  into 
the  patient.  According  to  Darier  some  diseases  are  affected  more  by 
one  than  the  other  of  these  agents  so  that  some  clinical  experience 
must  be  gained  before  it  is  possible  to  use  them  with  greatest  success. 

Quite  a  number  of  observers  have  reported  on  the  use  of  milk  in- 
jections in  the  treatment  of  ophthalmoblennorrhea,  among  them  Jickeli, 
Nassbaum,  v.  Liebermann,  Purtcher,  Mtiller,  Holler,  Sommer,  Honig 
and  Bachsteg,  all  but  the  latter  noting  marked  benefit  following  the 
milk  injections.  Liebermann  undertook  the  treatment  of  a  large  series 
of  cases  of  gonorrheal  ophthalmia  in  adults  with  milk  injections,  but 
at  the  same  time  did  not  fail  to  continue  the  usual  local  treatment. 
He  found  that  the  effect  of  the  injections  on  the  symptoms  was  as 
follows: — The  secretion  usually  ceased  after  the  first  or  the  second 
injection  and  only  rarely  recommenced.  The  demonstration  of  the 
organism  in  the  exudate  became  more  and  more  difficult  as  the  effect 
on  the  amount  of  secretion  became  apparent;  only  in  exceptional 
cases  did  he  obtain  a  positive  bacterial  finding  after  the  secretion  had 


DISEASES  OF  THE  EYE  239 

diminished.  The  primary  effect  of  the  injections  was  a  chemosis 
after  which  the  evidences  of  inflammation  rapidly  diminished.  Ulcers 
of  the  cornea  were  prevented;  if  already  present  they  were  arrested; 
Liebermann  observed  only  one  corneal  perforation  in  his  entire  series 
of  about  100  cases.  Liebermann  made  use  of  injections  of  a  manganese 
colloid  with  excellent  results. 

The  most  extensive  treatise  on  the  subject  has  been  published  by 
Uddgren  at  Stockholm,  while  other  Scandinavian  oculists  have  re- 
ported conflicting  results — Lundsgaard,  Andersen,  etc.  Uddgren  used 
milk  injections  (sterile  milk,  boiled,  with  very  little  reaction  on  the 
part  of  the  patient)  in  about  100  cases  of  eye  diseases.  The  results 
were  as  follows: — 

Conjunctivitis  czstivalis.     Three  cases.    Prompt  recovery. 

Trachoma.    Three  cases.    Improved. 

Conjunctivitis  phlyctenulosa.  Fifteen  cases.  All  improved,  subjec- 
tively as  well  as  objectively. 

Keratitis  parenchymatosa.  Fifteen  cases.  Of  these  twelve  positively 
luetic,  the  others  probably  tuberculous.  Results  inconclusive. 

Keratitis  profunda.  Five  cases.  Four  cured;  the  fifth  case  had  a  re- 
lapse after  three  months — panophthalmitis. 

Maculae  cornece.  Twenty -four  cases.  Improved  vision  in  some  cases; 
in  a  few  of  these  the  result  was  not  permanent. 

Scleritis  and  ScleroJceratitis.  Seven  cases.  Without  specific  therapy 
the  milk  injections  result  in  only  transient  improvement.  Combined  with 
specific  therapy  Uddgren  obtained  good  results. 

Iritis  and  Iridocyclitis.  Eight  acute  cases.  Cured  or  much  improved. 
Four  subacute.  Improved.  Four  chronic  plastic  type.  Improved. 

Opacitates  corp.  vitr.  Eleven  cases.  Stimulating  and  resorbing  effect 
of  the  injections  marked  in  some  cases. 

Ablatio  retina.     Three  cases.     No  permanent  improvement. 

Ocular  nerve  lesions.  Neuritis  improved  and  in  some  cases  complete 
cure.  Atrophy  of  nerve  not  improved  in  single  case  injected. 

Paresis  N.  abducent.    Two  cases.    Recovery  accelerated. 

Chevallier  has  used  collargol  intravenously  in  cases  of  septic  iritis 
and  in  keratitis  with  good  results,  while  Boyd  has  reported  good  results 
by  using  typhoid  vaccine  intravenously  in  cases  of  iritis.  Zimmer- 
mann  (Chas.)  has  reported  two  cases  of  corneal  infiltrations  which 
improved  after  milk  injections. 

Veach  has  recently  contributed  some  experimental  data  concern- 
ing the  value  of  nonspecific  therapy  in  ocular  infections  due  to  idio- 
pathic  origin.  Reber  has  in  his  classification  observed  that  iritis  is 
usually  due  to  one  of  5  organisms — the  spirochete,  the  tubercle  bacil- 
lus, the  gonococcus,  the  pneumococcus  and  the  influenza  bacillus. 
The  spirochete  is  responsible  for  some  30  to  60%  of  these.  Assuming 
that  we  have  sufficiently  satisfactory  therapy  for  all  these  specific  in- 
fections, there  still  remain  a  large  number  in  which  our  therapy  i§ 


240  PROTEIN  THERAPY 

seemingly  ineffectual,  cases  of  indefinite  etiology — rheumatic,  meta- 
bolic, etc.  It  is  for  this  group  that  Veach  considered  nonspecific 
therapy  of  utmost  usefulness. 

Veach  produced  experimental  iritis  by  injecting  streptococci,  both 
viridans  and  hemolyticus,  and  staphylococcus  aureus  into  the  iris  of 
rabbits.  These  were  then  treated  with  intramuscular  milk  injections. 
The  course  of  the  disease  in  the  treated  rabbits  was  definitely  short- 
ened as  compared  to  rabbits  similarly  infected  but  not  treated  with 
milk.  Veach  considers  the  experimental  results  sufficiently  encourag- 
ing to  warrant  the  use  of  this  nonspecific  method  of  therapy  in  clini- 
cal practice  in  all  cases  of  iritis  of  uncertain  origin. 

Stocker,  instead  of  injecting  milk  intramuscularly  in  eye  cases, 
has  used  it  intraperitoneally.  The  method  as  used  by  him  consists 
of  injecting  from  3  to  12  gm.  of  cow's  milk  (boiled  for  three  or  four 
minutes)  into  the  peritoneal  cavity.  A  fever  that  persists  for  from 
two  to  three  days  results.  His  results  in  eye  cases  have  been  very 
good. 

Musy  pasteurizes  milk  for  15  minutes  and  injects  5  c.c.  intra- 
gluteally  every  2  to  4  days.  He  was  amazed  to  observe  the  rapidity 
with  which  the  pain,  injection,  photophobia  and  the  swelling  diminish 
under  the  course  of  such  injections. 

In  iridocy clitic  processes  the  results  were  excellent;  in  iritis  the 
pain  subsided,  the  pupil  dilated  and  corneal  defects  showed  early 
vascularization ;  even  in  luetic  cases  with  the  formation  of  synechia?, 
the  milk  injection  assisted  the  systemic  specific  treatment. 

On  the  other  hand,  with  chronic  iridochoriocyclitis,  in  blennorrhea 
neonatorum  and  in  tuberculous  iridocyclitis  the  treatment  seemed  to 
have  little  effect  on  the  course  of  the  disease. 

Klingmueller  reported  that  with  turpentine  injections  five  cases 
of  ophthalmoblennorrhea  cleared  up  very  promptly. 

Peltesohn  has  studied  in  particular  scrofulous  diseases  of  the 
eye  and  their  treatment  by  nonspecific  means  and  by  the  Ponndorf 
method  of  intracutaneous  tuberculin  treatment.  He  found  that  the 
severe  and  moderately  severe  cases  responded  well  to  the  latter 
method  while  almost  hopeless  cases  were  very  favorably  influenced  by 
suitable  combined  treatment  with  the  casein  and  the  tuberculin 
injections. 

The  report  of  Heine  must  finally  be  mentioned.  Heine  reports 
the  results  of  his  experiments  with  subcutaneous  injections  of  milk  in 
albuminuric  retinitis.  The  dosage  was  from  5  to  10  c.c.  If  we  re- 
gard the  checking  of  the  deterioration  of  vision  as  due  in  all  cases 
to  the  milk  injections,  then  out  of  17  eyes,  15  were  favorably  affected 
thereby.  If  we  consider  only  such  cases  as  being  favorably  affected 
in  which  there  was  a  marked  improvement  of  vision,  the  favorable 
results  numbered  11,  whereas  in  4  the  disease  process  was  only  stayed. 
In  0Bly  2  did  the  disease  process  continue  in  spite  of  the  injections. 


DISEASES  OF  THE  EYE  241 

Also  a  series  of  cases  of  infectious  retlnitis  and  choroiditis  was  treated 
with  milk  injections.  The  primary  results  were  often  excellent,  though 
recurrences  were  common.  Schwarte  treated  a  series  of  severe  infec- 
tious processes  with  milk  injections  and  reports  that  the  results  were 
very  apparent,  most  of  the  cases  being  favorably  influenced. 


CHAPTER  XVII 
INFLAMMATION 

The  studies  that  have  been  made  in  recent  years  which  deal  with 
the  healing  of  wounds  and  the  factors  that  favor  or  retard  bacterial 
growth  in  wounds  have  added  much  to  our  understanding  of  the 
fundamentals  of  local  infection  and  resistance. 

We  must  keep  in  mind  the  following  facts.  Injured  tissue — con- 
tused— burned — fragmented  or  altered  to  such  a  degree  that  its  cir- 
culation is  markedly  interfered  with  is  a  twofold  source  of  intoxica- 
tion. As  it  becomes  necrotic — even  though  sterile — it  produces  protein 
split  products  which  are  profoundly  toxic  to  the  organism  and  cause 
either  a  febrile  reaction  if  relatively  small  in  amount,  or  complete 
prostration  and  shock  if  larger  in  amount.  Very  likely  the  mere 
liberation  of  tissue  (cell)  juices  without  digestion  can  bring  about 
similar  effects;  in  animal  experimentation  the  toxicity  of  the  tissue 
extracts  is,  of  course,  well  known,  where  their  effect  on  the  coagulation 
mechanism  usually  brings  about  an  acute  shock  picture  and  death. 
Nageli  has  emphasized  the  importance  of  tissue  necrosis,  even  when 
aseptic,  in  general  pathological  problems.  Experimentally  it  has  been 
found  that  the  products  of  tissue  contusion  can  kill  an  animal  and 
the  investigations  on  the  production  of  shock  made  during  the  recent 
war  by  a  number  of  American  investigators  have  also  served  to  focus 
our  attention  on  this  practical  problem.  Nageli,  among  other  experi- 
ments, took  small  pieces  of  tissue,  permitted  them  to  autolyze  for  24 
hours  aseptically  and  found  that  on  reimplantation  the  animal  died 
as  a  result  of  the  absorption  of  the  toxic  split  products  from  the  auto- 
lyzing  material.  Even  sterile  blood  (autogenous)  will,  when  free  in 
the  tissues,  cause  a  considerable  leukocytosis  (Dold),  and  Freund 
has  recently  published  interesting  studies  that  demonstrate  the  forma- 
tion of  toxic  substances  from  blood.  Secondly,  the  altered  tissue  per- 
mits the  establishment  of  bacterial  invasion  against  which  normal 
tissues  would  be  amply  able  to  protect  themselves. 

For  the  first  twelve  or  twenty-four  hours  following  injury  (the 
so-called  preinflammatory  stage)  infecting  organisms  are  confined  to 
the  surface  of  such  wounds.  If  during  this  period  the  injured  tissue 
is  excised  (debridement)  we  remove  the  potential  sources  of  intoxica- 
tion as  well  as  the  opportunity  for  infection,  and  healing  by  primary 
intention  is  the  rule. 

When  once  this  pre-inflammatory  stage  has  been  passed  and  bac- 

242 


INFLAMMATION  243 

teria  have  found  lodgment  and  have  become  established,  then  we 
have  to  deal  with  the  invasive  power  of  the  organisms  on  the  one 
hand  and  the  factors  of  resistance  of  the  body  on  the  other.  To 
Wright  we  are  considerably  indebted  for  his  contributions  to  this 
particular  field  and  Flemming  has  discussed  the  subject  in  a  compre- 
hensive manner  in  a  recent  paper. 

According  to  his  view  the  role  of  antiseptics  in  the  treatment  of 
wound  infection  is  problematic.  Flemming  believes  that  all  solutions 
that  are  at  all  effective  have  no  appreciable  bactericidal  titer  in  the 
wound,  but  that  they  act  as  mild  tissue  irritants  leading  to  increased 
leukocytic  emigration  and  to  more  abundant  flooding  of  the  wound 
with  normal  tissue  fluids,  in  this  way  hastening  the  separation  of 
sloughs  and  the  elimination  of  bacteria.  He  regards  the  antiseptic 
method  of  Dakin  and  Carrel,  for  instance,  as  fundamentally  dependent 
on  the  same  principles  as  that  of  the  so-called  physiologic  method  of 
Wright. 

It  is  quite  apparent  from  his  study  that  both  the  leukocytes  as 
well  as  the  enzyme-antienzyme  content  of  the  blood  serum  and  tis- 
sue fluids  have  considerable  bearing  on  the  healing  of  wounds. 

Application  of  these  principles  was  made  by  Wright  in  the  use  of 
hypertonic  salt  solutions  (clinically  not  successful  to  the  degree  an- 
ticipated, because  of  the  discomfort  to  the  patient) ;  the  use  of  concen- 
trated sugar  solutions;  and  the  use  of  nonpathogenic  bacteria  which, 
when  introduced  into  the  wound,  seemed  to  have  a  favorable  effect 
on  inflammation.  The  so-called  "Reading"  bacillus  seems  to  have 
been  one  of  the  most  successful  of  the  bacteria  of  this  type.  This 
was  a  spore  bearing  anaerobe  of  saprophytic  nature,  to  which  the 
name  "Reading  Bacillus"  was  given  by  Donaldson.  He  describes  it 
as  follows: 

"It  is  highly  resistant  to  heat  and  drying,  and  grows  best  in  a 
slightly  alkaline  medium.  It  most  closely  resembles  B.  sporogenes 
(Metchnikoff) .  It  is  nonpathogenic  for  animals  as  well  as  for  man 
when  introduced  into  septic  wounds.  It  does  not  attack  living  tis- 
sues. The  use  of  salt  is  not  necessary  for  the  successful  treatment 
of  gunshot  wounds,  as  was  thought  by  those  who  advocated  the  salt- 
bag  method.  The  success  depends  rather  on  the  activity  of  this 
particular  bacillus  under  conditions  favorable  to  its  growth  and  not 
on  the  salt.  The  rationale  of  the  method  depends  not  on  inhibition 
by  the  Reading  bacillus  of  the  growth  of  pathogenic  organisms  in  the 
wound  either  by  reason  of  the  formation  by  the  bacillus  of  an  in- 
hibitory organic  acid,  or  by  the  production  of  any  bacteriolytic  fer- 
ment. It  acts,  however,  by  virtue  of  its  proteoclastic  enzymes  as  an 
organic  catalyst  which  hydrolyzes  the  substrate  of  dead  protein.  It 
disintegrates  the  protein  base  from  which  pathogenic  organisms  oper- 
ate, and  while  so  doing  does  not  itself  give  rise  to  fresh  toxic  sub- 
stances. Not  only  so,  but  it  is  probably  able  to  hydrolyze  also  the 


244  PROTEIN  THERAPY 

toxic  degradation  products  of  other  organisms.  In  support  of  this 
theory,  a  resume  is  given  of  experiments  on  tetanus  and  other  toxins, 
which  show  that  the  Reading  bacillus,  out  of  a  series  of  organisms 
investigated,  is  alone  able  to  reduce  the  toxicity  of  these  toxins.  There 
is  one  exception,  namely,  B.  sporogenes  (Metchnikoff) ,  which,  how- 
ever, does  not  appear  to  be  so  potent  in  this  direction  as  is  the  Read- 
ing bacillus."  Donaldson  suggests  that  this  ability  to  modify  a 
toxin  like  that  of  tetanus  may  prove  to  be  of  value  as  a  means  of 
differentiating  various  types  of  proteolytic  organisms,  while  it  in- 
troduces new  ideas  in  regard  to  the  biologic  processes  going  on  in 
septic  gunshot  wounds. 

In  the  discussion  of  the  effect  of  nonspecific  injections  on  the  bubo, 
the  influence  of  the  enzyme  and  antienzyme  changes  have  been  fully 
discussed  in  their  bearing  on  local  inflammatory  processes,  so  that 
it  will  not  be  necessary  to  repeat  the  conception  of  the  mechanism  in- 
volved. It  should  be  kept  in  mind,  however,  that  the  effect  of  non- 
specific injections  is  a  diphasic  one:  we  deal  at  first  with  a  peripheral 
leukopenia,  a  lowering  of  the  antiferment  titer,  an  increase  in  the  pro- 
tease, an  increase  in  the  permeability  of  the  capillaries,  in  the  irritabil- 
ity of  the  nervous  system,  most  probably  an  increase  in  the  suscepti- 
bility to  intoxication.  This  is  the  negative  phase  which  makes  its  effect 
apparent  on  local  inflammatory  changes  by  an  increase  in  the  symp- 
tomatology. This  phase  is  followed  by  a  positive  one  in  which  the  re- 
verse of  all  these  biological  alterations  takes  place,  and  usually  to  a  de- 
gree measured  by  the  intensity  of  the  preceding  negative  phase.  On  the 
basis  of  this  mechanism  we  can  determine  to  a  certain  degree  what  we 
may  expect  from  nonspecific  therapy  and  what  its  limitations  will  be. 
If,  for  instance,  we  have  existing  a  large  inflammatory  focus  with 
much  absorption  of  necrotic  material,  with  a  marked  leukocytic  re- 
action and  a  high  temperature,  nonspecific  therapy  will  be  abso- 
lutely without  effect  in  the  majority  of  cases  because  the  absorption 
from  the  inflammatory  focus  is  already  doing  the  same  thing  that 
we  would  attempt  artificially.  In  a  phlegmon  the  treatment  is  sur- 
gical, not  expectant  or  nonspecific.  On  the  other  hand,  in  a  lym- 
phangitis or  a  lymphadenitis,  as  Kaiser  has  shown,  excellent  results 
may  follow  nonspecific  injections  just  as  they  do  in  the  case  of  the 
bubo. 

Despite  the  fact  that  Gellhaus  has  reported  favorable  results  in 
the  treatment  of  appendicitis  by  means  of  collargol  injections  (in  34 
cases  only  6  were  operated)  the  fact  that  the  nonspecific  injection  is 
first  followed  by  a  negative  phase  with  intensification  of  the  disease 
process  would,  in  my  judgment,  definitely  exclude  all  such  and  similar 
acute  surgical  conditions  from  the  field  of  its  application. 

Gellhaus  has  reported  on  a  very  extended  series  of  cellular  inflam- 
mations (143  cases)  treated  with  intravenous  injections  of  small  doses 
of  collargol  and  seems  very  much  impressed  with  the  possibilities. 


INFLAMMATION  245 

In  31  cases  of  cellulitis  17  healed  without  surgical  interference.  Schu- 
bert, on  the  other  hand,  tried  turpentine  injections  in  80  surgical 
cases  of  all  kinds,  but  his  results  were  not  satisfactory;  Wederhake 
and  Chiaudano  have  also  given  the  method  a  trial,  the  latter  with 
success  in  mastitis. 

On  old  chronic  inflammation  and  sluggish  ulcers  much  more  can 
be  expected  and  a  number  of  favorable  reports  have  been  published. 
Gow,  for  instance,  treated  an  old  sluggish  ulcer  with  intravenous  in- 
jection of  streptococci,  using  a  dosage  of  100  million,  with  good  re- 
sults. In  this  case  the  reaction  was  delayed  considerably  as  com- 
pared to  the  reaction  that  follows  typhoid  or  colon  injection.  The 
pulse  rate  showed  some  change  after  4  hours  but  the  febrile  rise  did 
not  begin  until  about  10  hours  after  the  injection.  There  was  some 
nausea  and  a  headache  which  began  twelve  hours  after  the  injection 
and  persisted  for  36  hours.  There  was  practically  no  leukocytic  re- 
sponse. 

Zalewski  and  Miiller  have  also  reported  on  the  treatment  of  old 
ulcers  and  more  recent  wounds  with  milk  injections  (aolan)  and  ob- 
tained very  satisfactory  results. 

Heterovaccination  has  found  many  adherents  among  French  clini- 
cians, and  in  a  recent  discussion  of  the  Societe  de  Chirurgie  at  Paris 
the  treatment  (especially  by  the  method  of  Pierre  Delbet) ,  particularly 
of  carbuncles  and  similar  surgical  conditions,  was  taken  up.  Pierre 
Delbet  combines  the  Pasteur  method  of  attenuated  cultures  with  the 
modern  method  of  killed  cultures.  He  found  it  possible  by  this 
means  to  inject  a  considerably  larger  dose,  several  billions  of  micro- 
organisms, at  one  time.  Despite  the  massive  dose,  he  has  never  ob- 
served any  reaction  analogous  to  that  described  by  Wright  as  the 
negative  phase,  which  Delbet  thinks  is  the  result  of  an  excessive 
initial  dose.  On  the  contrary,  certain  toxic  reactions  were  observed, 
often  very  violent,  and  despite  their  intensity,  these  were  found  to 
constitute  a  good  omen.  In  the  process  of  aging,  the  toxicity  of  the 
culture  is  probably  attenuated  though  not  entirely  destroyed.  After 
some  attempts,  Delbet  fixed  on  4  c.c.,  representing  about  thirteen 
billions  of  organisms,  as  a  safe  and  effective  dose.  The  vaccine  is, 
naturally,  a  stock  vaccine  of  streptococcus,  staphylococcus  and  Bacillus 
pyocyaneus  (the  last  in  great  abundance:  eight  billions).  Delbet  be- 
lieves it  unnecessary  to  use  the  specific  micoorganism  and,  like 
Wright,  he  has  not  only  abandoned  autogenous  vaccines,  but  he  even 
questions  whether  better  results  are  not  obtained  with  a  vaccine  pre- 
pared from  cultures  of  a  micoorganism  other  than  that  which  is 
the  causative  agent  in  a  given  case.  The  method  has  been  employed 
since  1913,  since  which  time  no  case  of  carbuncle  in  Delbet's  service 
has  been  treated  by  surgical  incision ;  boils,  lymphangitis  and  erysipe- 
las also  respond  very  promptly  to  this  treatment. 

Renaud  has  used  typhoid  vaccines  in  the  treatment  of  phlegmons, 


246  PROTEIN  THERAPY 

while  Hofer  found  that  he  at  times  obtained  very  satisfactory  results 
from  milk  injections  in  carbuncles  and  phlegmons. 

A  related  procedure  is  that  of  the  production  of  a  nonspecific  reac- 
tion before  some  surgical  procedure  in  order  to  make  the  patient  more 
resistant  to  infection  and  a  considerable  literature  of  rather  incon- 
clusive nature  has  been  accumulated.  Nucleins  were  the  favorite 
agents,  injections  being  made  usually  from  36  to  48  hours  previous 
to  laparotomies  in  order  to  prevent  peritonitis.  De  Paoli  and  Calisti, 
for  instance,  report  on  two  hundred  cases  in  which  such  injections 
were  made  and  an  increased  resistance  against  infection  claimed. 
Experimentally  they  determined  that  apart  from  the  leukocytosis  pro- 
duced by  such  injections,  bactericidal  substances  for  colon  bacilli 
could  be  demonstrated  in  increased  amounts  after  the  injections. 

Stracker  used  milk  injections  with  the  idea  of  increasing  the  gen- 
eral resistance  of  patients  before  operation  and  utilized  reamputation 
cases  for  the  purpose.  He  had  observed  that  in  old  infected  stumps 
subjected  to  reamputation,  infection  of  the  new  area  was  almost  a 
constant  result  because  of  the  poor  condition  of  the  patient  generally 
and  because  of  the  lowered  local  resistance  of  the  tissues.  To  in- 
crease the  resistance  he  injected  10  c.c.  of  sterile  milk  three  times  be- 
fore the  operation,  at  two-day  intervals.  In  fully  half  of  the  cases 
he  observed  a  focal  reaction  at  the  site  of  the  old  lesion.  His  results 
were  as  follows: — In  43  cases  of  reamputation  without  preceding  milk 
injections  10%  healed  by  primary  intention;  in  72  cases  with  pre- 
ceding milk  injection  49%  healed  by  primary  intention.  In  37% 
of  the  former  cases  there  was  suppuration,  while  in  the  "milk"  series 
only  13%  suppurated. 

Closely  related  to  these  observations  is  the  observation  made  by 
Stuhl,  that  infected  wounds  heal  more  rapidly  after  typhoid  inocula- 
tions. Perhaps  the  recent  paper  of  Bier's  as  well  as  the  discussion 
which  followed  its  presentation  at  the  Berlin  Medical  Society  will  be 
found  of  particular  interest  because  it  covers  in  a  broad  way  the 
entire  subject  of  inflammation  and  our  present  methods  of  therapy, 
with  specific,  nonspecific  and  physical  means. 


CHAPTER  XVIII 
INDICATIONS  AND   CONTRA-INDICATIONS 

Protein  therapy  offers  a  potent,  perhaps  the  most  potent,  method 
that  we  have  at  our  command  of  altering  the  current  of  cellular 
activity  in  two  diametrically  opposite  directions — acceleration  of 
function  and  depression  of  function.  If  the  agent  that  we  inject  is 
very  toxic  and  the  dose  large,  acceleration  soon  gives  place  to  fatigue, 
to  complete  exhaustion  and  finally  to  death;  if  relatively  large  doses 
are  repeatedly  given  the  condition  of  protein  cachexia,  observed  in 
experimental  animals,  might  supervene.  Proper  dosage,  on  the  other 
hand,  results  in  transient  but  well  marked  stimulation  without  clini- 
cally apparent  fatigue,  and  if  continued  for  a  period  of  time  the  altera- 
tion of  acceleration  and  depression  of  metabolic  processes  becomes 
clinically  manifest  in  increased  weight  and  general  well  being. 

It  is  apparent  how  far-reaching  the  field  of  application  must  be 
and  how  difficult  to  make  definite  rules  of  procedure  or  to  advocate 
certain  methods  or  preparations.  The  extent  of  usefulness  of  a  method 
that  is  a  true  "plasmaactivation"  in  the  strict  sense  of  the  term  for- 
bids a  definite  delimitation  to  narrow  confines.  But  despite  theoretical 
possibilities,  actual  practice  might  perhaps  reduce  the  clinical  appli- 
cation to  very  modest  dimensions.  In  this  connection  I  would  quote 
the  opinion  of  Schmidt,  who  believes  that  we  shall  some  day  come 
to  regard  a  course  of  protein  therapy  in  the  same  light  that  we  now 
do  a  changetin  diet,  a  change  in  climate,  a  course  of  baths ;  that  is,  apart 
from  its  usefulness  in  acute  diseases,  we  shall  accept  protein  therapy 
in  its  various  modifications  as  one  of  the  very  first  and  the  most  com- 
monplace*of  methods  of  therapy. 

With  these  considerations  in  mind  we  can  intelligently  apply 
protein  therapy  in  infectious  diseases  only  if  we  fix  very  firmly  the 
concept  that  nonspecific  therapy  is  purely  a  method  of  stimulation 
whereby  all  the  forces  of  cellular  and  humoral  resistance  are  for  a 
short  period  of  time  keyed  to  the  very  highest  pitch  and  by  reason 
thereof,  stimulation  of  this  character  is  useless  when  the  cells  of  the 
body  are  profoundly  fatigued. 

As  with  other  new  therapeutic  procedures  there  is  still  some  un- 
certainty as  to  the  proper  dosage.  Especially  is  this  true  because 
the  dosage  depends  to  some  extent  on  the  vigor  of  the  patient,  on 
the  type  of  infection  which  is  causing  the  disease,  as  well  as  on  the 
stage  of  the  disease.  There  is  no  unanimity  of  opinion  whether  it 

247 


248  PROTEIN  THERAPY 

is  well  to  give  one  or  two  fairly  large  injections  or  several  smaller 
ones.  Whatever  method  is  used  it  is  well  to  be  cautious,  especially 
when  dealing  with  such  toxic  substances  as  vaccines. 

Before  applying  the  treatment  to  any  acute  disease  it  would  seem 
that  prudence  would  demand  a  thorough  familiarity  with  the  range 
of  the  reaction  and  the  degree  of  toxicity  of  the  preparation  it  is 
intended  to  us,  by  first  employing  it  in  some  arthritic  cases.  In 
arthritis,  when  we  exclude  alcoholics  and  old  cardiac  cases,  the  dangers 
of  untoward  effects  from  the  reaction  are  minimal  and  with  reasonable 
caution  nonspecific  therapy  is  not  only  without  risk  but  indeed  fre- 
quently followed  by  gratifying  clinical  improvement.  Only  in  the 
light  of  experience  so  gained  would  it  seem  permissible  for  us  to 
attempt  to  extend  this  form  of  therapy  to  other  acute  infections. 

In  general  it  is  to  be  kept  in  mind  that  injections  must  be  given 
early  in  the  course  of  the  disease;  that  the  injections  should  be  given 
slowly;  that  relatively  small  doses  should  be  given  the  first  time  and 
that  care  must  be  taken,  if  intramuscular  injections  are  made,  that 
the  injection  is  not  by  accident  intravenous. 

For  intravenous  injections  the  protein  split  products  are,  for  obvi- 
ous reasons,  more  satisfactory  than  vaccines;  if  a  relatively  mild  re- 
action is  desired  the  various  serums  are  very  useful.  Where  a  mod- 
erate reaction  (general  and  focal)  is  desired,  intramuscular  injections 
of  boiled  market  milk  are  to  be  considered;  if  less  general  but  some 
focal  effect  is  desired,  Uddgren  believes  that  milk  with  a  low  bacterial 
count  (certified  milk)  is  to  be  preferred. 

The  possibility  of  a  certain  degree  of  selective  action  of  some  of  the 
agents  is  not  to  be  ignored,  the  use  of  staphylococcus  and  pyocyaneus 
vaccine  mixtures  in  the  treatment  of  neuritis  being  such  a  case.  In 
hemorrhagic  disease  the  use  of  serums  and  of  milk  or  salt  solutions 
is  to  be  preferred  to  vaccine  or  proteose  injections,  because  of  more 
marked  effects  in  hemostasis. 

It  should  not  be  necessary  to  point  out  that  the  nonspecific  method 
of  treatment  should  under  no  circumstances  be  considered  as  a  rival 
or  a  substitute  for  the  proven  specific  measures  that  we  have  at  our 
command.  That  a  nonspecific  factor  is  at  times  and  possibly  often 
associated  with  the  specific  reaction  may  be  true,  the  more  reason 
that  both  should  be  studied  and  both  utilized  in  their  proper  time 
and  place.  From  the  evidence  so  far  gathered,  the  use  of  the  spe- 
cific measures  is  always  in  place  whenever  a  true  toxin  is  to  be 
neutralized  by  an  antitoxin;  on  the  other  hand,  the  nonspecific  meas- 
ures find  a  field  of  usefulness  as  adjuvants  of  drug  therapy  in  the 
treatment  of  syphilis,  both  early  and  late,  with  quinin  in  malaria, 
with  salicylates  in  arthritis,  with  luminal  in  epilepsy,  etc.  Here  the 
injections  serve  at  least  two  purposes.  They  facilitate  the  diffusion 
and  distribution  of  the  drug  and  they  increase  the  general  resistance 
of  the  patient. 


INDICATIONS  AND  CONTRA-INDICATIONS          249 

Apart  from  the  early  use  of  the  nonspecific  agents  in  the  hemor- 
rhagic  diseases,  their  use  in  methods  of  desensitization,  not  only  in 
cases  of  asthma  where  we  can  find  no  specific  cause,  but  in  angioneu- 
rotic  edema,  urticaria  and  certain  of  the  gastro-intestinal  conditions 
to  which  Danysz  has  given  particular  attention,  is  one  of  consider- 
able importance. 

Finally  we  have  to  keep  before  use  the  therapeutic  application  of 
these  agents  in  the  focal  reaction,  where  both  the  sharp  effect  of  in- 
travenous vaccine  injections  (as  in  iritis)  and  the  milder  effect  of 
repeated  injections  of  turpentine  have  found  definite  spheres  of  use- 
fulness. 

CONTRA-INDICATIONS 

The  effort  has  been  made  throughout  this  treatise  to  make  it  clear 
that  the  nonspecific  reaction  is  a  diphasic  reaction,  the  first  effect  be- 
ing the  intensification  of  the  disease  manifestation  both  generally  and 
locally,  the  second  being  a  constructive  phase  in  which  there  occurs 
a  general  euphoria,  a  diminution  of  disease  symptoms  both  generally 
and  locally,  with  at  times  complete  restitution  to  the  normal.  Gen- 
erally speaking  it  has  been  found  that  the  more  severe  the  first  phase 
the  greater  the  clinical  benefit.  This  augmentation  of  the  disease 
symptoms  must  be  kept  firmly  in  mind.  No  patient  should  be  sub- 
jected to  an  intravenous  injection  normally  followed  by  a  severe 
reaction  (typhoid  or  colon  bacilli,  protein  split  products,  etc.)  unless 
there  is  every  evidence  that  the  patient  is  a  good  clinical  risk  and 
able  to  bear  the  additional  strain  imposed  by  the  injection.  If  non- 
specific therapy  is  desirable  in  the  more  uncertain  cases  some  of  the 
less  severe  methods  can  be  employed  with  much  less  danger,  such 
as  intramuscular  injections  of  milk,  nucleins,  turpentine,  etc.  An- 
other and  equally  important  deduction  can  be  drawn  from  the  recogni- 
tion that  the  reaction  is  a  diphasic  one  that  depends  on  stimulating 
the  cells.  Therapeutic  results  cannot  be  expected  when  the  organism 
is  no  longer  capable  of  response  to  stimulation.  When  complete 
fatigue  has  been  reached  no  amount  of  stimulation  will  avail  and 
the  additional  burden  imposed  by  the  material  injected  can  only  harm 
the  patient. 

One  observes  not  infrequently  in  the  American  literature  the  use  of 
relatively  large  doses  of  such  agents  as  typhoid  vaccine,  colon  vaccine 
and  similarly  toxic  substances.  It  would  appear  to  be  not  only  neces- 
sary but  quite  irresponsible  to  subject  patients  to  such  severe  methods. 
One  can  usually  obtain  a  very  satisfactory  reaction  with  moderate 
dosage  and  this  without  unusual  risk  or  inconvenience  to  the  patient. 

Particular  care  must  be  observed  to  obtain  a  history  of  hyper- 
sensitiveness  on  the  part  of  the  patient — serum  sickness — asthma — 
urticaria — angioneurotic  edema — or  of  epilepsy  or  other  grave  ner- 
vous instability.  In  such  cases  the  more  active  agents  must  not  be  used. 


250  PROTEIN  THERAPY 

Alcoholism,  of  the  type  that  one  encounters  not  infrequently  in 
charity  hospitals,  is  an  absolute  contra-indication.  We  have  records 
of  several  patients  who  developed  delirium  tremens  after  nonspecific 
injections,  one  ending  fatally. 

Pregnancy  must  be  similarly  regarded  as  an  absolute  contra- 
indication. 

In  the  various  cardiac  lesions  great  caution  must  be  observed. 
We  would  include  not  only  severe  valvular  injuries  but  cases  with 
high  blood  pressure,  with  arteriosclerosis,  myocarditis,  or  with  evi- 
dences of  vasomotor  instability.  In  typhoid  we  have  found  it  a  good 
rule  to  exclude  all  cases  with  a  pulse  rate  over  100;  indeed,  every 
case  of  acute  infectious  disease  should  be  carefully  gone  over  for  evi- 
dence of  myocardial  impairment  before  injections  are  made.  In  well 
compensated  valvular  lesions  we  have  injected  typhoid  vaccine  with 
relatively  severe  general  reactions  without  ill  effects.  The  left  heart 
border  may  be  observed  to  extend  outward  for  a  centimeter  or  so, 
but  as  a  rule  there  are  no  evidences  of  decompensation,  v.  Groer 
has  fortified  patients  that  were  not  in  exceptionally  good  vascular 
tone  by  giving  small  doses  of  digitalis  for  about  two  days  before 
injections  were  made. 

Diabetes  is  considered  a  contra-indication  by  Lindig  who  was  of 
the  impression  that  because  of  the  vascular  changes  often  associated 
with  the  diabetic  condition  the  diabetic  should  be  excluded.  Uddgren 
also  excludes  the  diabetic. 

In  typhoid  we  have  excluded  the  older  cases  (third  week)  from 
treatment,  as  well  as  cases  that  were  septic  or  had  evidence  of  septic 
or  pulmonary  complications.  Naturally  any  evidence  of  bleeding 
either  from  the  nose,  stomach  or  bowel  would  exclude  nonspecific 
therapy.  The  earlier  workers  observed  several  deaths  from  epistaxis 
following  intravenous  typhoid  injections  when  these  precautions  were 
not  observed. 

Neither  old  age  nor  infancy  is  considered  a  contra-indication  by 
Uddgren. 

The  patient  does  not  become  sensitive  to  the  injection  of  hetero- 
vaccines  or  of  proteoses;  on  the  contrary,  with  succeeding  doses  there 
is  increased  tolerance  until  several  multiples  of  the  original  dose  must 
be  injected  to  elicit  the  proper  reaction.  Sensitization  to  serum  is 
not  only  possible  but  occurs  not  infrequently,  usually  not  to  any 
degree  that  need  cause  alarm.  Smith  has  made  use  of  this  increased 
sensitization  to  serum  to  obtain  shock  reactions  and  therapeutic  re- 
sults therefrom.  With  milk  the  conditions  are  somewhat  different. 
Some  observers,  including  Bessau,  Decastello  and  Mueller,  consider 
the  milk  injection  and  its  effect  as  due  practically  to  the  bacterial 
content,  i.e.,  a  heterobacteriotherapy.  Considering  the  popularity  of 
the  milk  injections  in  Europe,  there  have  been  relatively  few  reports 


INDICATIONS  AND  CONTRA-INDICATIONS  251 

of  sensitization  from  it,  or  severe  collapse  following  after  repeated 
doses.  It  has  been  suggested  that  this  is  due  to  the  fact  that  the 
milk  is  boiled  and  so  dedifferentiated.  Hecht  made  intracutaneous 
injections  of  milk  in  patients  injected  previously  with  milk  and  also 
in  noninjected  patients.  There  was  no  difference  in  the  skin  response, 
nor  was  he  able  to  demonstrate  milk  antibodies. 

When  heterobacteriotherapy  was  first  introduced  and  the  dosage 
and  the  results  were  very  uncertain,  deaths  incident  to  the  injec- 
tions, such  as  were  reported  by  Eggerth,  Kraus  and  Mazza,  Boral, 
v.  Reuss  and  others,  were  perhaps  excusable.  Large  doses  of  typhoid 
vaccines  were  used  because  of  the  impression  that  such  amounts  were 
essential  to  elicit  the  reaction.  With  further  experience  such  disasters 
have  been  eliminated  and  less  violent  methods  have  come  into  use 
whenever  the  patient  is  not  in  good  condition.  Untoward  results  can 
no  longer  be  attributed  to  a  fault  in  the  method  of  therapy  but  to  the 
judgment  of  the  physician. 

Needless  to  say,  nonspecific  therapy  does  require  judgment,  care- 
ful attention  and  bedside  study  on  the  part  of  the  physician,  perhaps 
in  greater  measure  than  any  other  therapeutic  procedure.  It  should 
never  be  a  routine;  to  be  useful  it  must  be  an  individualized  therapy, 
with  dosage  and  preparation  and  time  of  application  varied  to  the  dis- 
ease, its  intensity,  its  duration  and  the  resistance  of  the  patient. 
So  used,  nonspecific  therapy  should  prove  to  be  one  of  our  most  use- 
ful measures  both  in  acute  infectious  diseases  and  chronic  inflamma- 
tory lesions. 


APPENDIX 
THE  PROTEINS  AND  THEIR  SPLIT  PRODUCTS 

The  nonspecific  reaction,  as  we  have  seen,  is  elicited  most  fre- 
quently by  colloidal  substances,  either  injected  therapeutically  or 
originating  in  the  tissues  as  a  result  of  some  inflammation  (turpen- 
tine injection,  burn,  trauma,  etc.).  Luithlen  has  as  a  result  used  the 
term  "Colloidal  Therapy"  to  designate  the  form  of  treatment.  Of 
the  various  colloids  we  find  the  proteins  and  their  derived  products 
most  commonly  used  and  it  may  be  proper,  therefore,  to  review  very 
briefly  the  salient  facts  concerning  their  classification,  structure  and 
behavior. 

The  native  proteins  consist  of  exceedingly  complex  molecules  which 
in  turn  are  built  up  of  combinations  of  amino  acids.  The  final 
molecule  is  a  large  one,  does  not  diffuse  through  parchment,  collodion 
or  animal  membrane,  frequently  gives  a  faint  opalescence  in  solu- 
tion, is  usually  amorphous  but  when  in  pure  form  can  be  crystallized 
under  certain  conditions.  Chemically  the  proteins  are  relatively 
stable  and  inert  and  are  amphoteric,  combining  with  both  the  hydro- 
gen and  the  hydroxyl  ion.  They  can  be  hydrolyzed  both  by  acids  and 
alkalies  as  well  as  by  enzymes,  yielding  a  series  of  degradation 
products  commonly  referred  to  as  protein  split  products.  These  lat- 
ter vary  in  character,  in  amount,  and  in  composition  with  the  protein 
undergoing  lysis,  the  method  used  in  bringing  about  the  disintegration, 
and  the  time  at  which  the  material  is  examined. 

For  convenience  we  may  use  the  so-called  American  classification 
of  the  proteins  which  divides  them  into  three  main  classes: 

A.  Simple  proteins. 

B.  Conjugate  proteins. 

C.  Derived  proteins. 

The  Simple  (or  Native)  Proteins.— These  are  naturally  occur- 
ring proteins  which  on  hydrolysis  yield  only  a-amino  acids  or  their 
derivatives. 

Albumins. — Simple  proteins,  coagulable  by  heat,  soluble  in  water 
and  dilute  salt  solutions.  Ovalbumin,  serum  albumin  belong  to  this 
group.  On  injection  they  are  followed  by  little  or  no  reaction  unless 
the  organism  has  been  previously  sensitized. 

Globulins. — Simple  proteins,  heat  coagulable,  insoluble  in  water 
but  soluble  in  dilute  solutions  of  salts  of  strong  bases  or  acids.  Serum 
globulin  is  an  example. 

252 


APPENDIX  253 

Glutelins. — Simple  proteins,  heat  coagulable,  insoluble  in  water  or 
dilute  salt  solutions,  but  soluble  in  very  dilute  acids  or  alkalies. 

Prolamins. — Simple  proteins,  insoluble  in  water  but  soluble  in 
80%  alcohol. 

Albuminoids. — Simple  proteins,  insoluble  in  dilute  acid,  alkali, 
water  or  salt  solution. 

Histons. — Simple  proteins,  not  coagulable  by  heat,  soluble  in 
water  and  dilute  acids;  strongly  basic. 

Protamins. — Simple  proteins,  basic,  noncoagulable  by  heat,  sol- 
uble in  ammonia. 

As  far  as  the  use  of  these  substances  in  nonspecific  therapy  is  con- 
cerned interest  has  centered  so  far  almost  wholly  on  the  native  pro- 
teins of  the  serum,  including  serum  albumin  and  globulin  as  well  as 
fibrinogen.  If  the  proteins  used  for  injection  include  plant  pro- 
teins, other  members  of  this  group  will,  of  course,  be  involved.  No 
study  has  been  made  dealing  with  the  relative  advantage  or  dis- 
advantage of  various  native  proteins  for  therapeutic  injections. 

The  Conjugated  (or  Compound)  Proteins. — These  are  compounds 
of  some  simple  protein  with  some  nonprotein  group,  the  latter  usually 
acid  in  nature.  They  are  subdivided  as  follows: 

Chromoproteins  (Hemoglobins). — These  are  proteins  in  which 
the  nonprotein  addition  group  is  colored,  as  hematin  in  hemoglobin. 

Glycoproteins  (Glucoproteins) . — The  prosthetic  group  in  this  class 
contains  a  carbohydrate  radical.  Mucin  and  cartilage  are  examples. 

Phosphoproteins. — Proteins  derived  from  the  cytoplasm.  The  ad- 
dition group  contains  phosphoric  acid.  Casein  belongs  to  this  group. 

Nucleoproteins. — Proteins  of  the  nucleus,  i.e.,  chromatin.  Nucleic 
acid  is  here  the  added  radical.  Nuclein,  nucleohiston,  etc.,  are  ex- 
amples. 

Lecithoproteins. — These  have  not  been  isolated  in  pure  form.  To- 
gether with  the  Lipoproteins  their  existence  is  probable,  the  former 
consisting  of  proteins  to  which  lecithins  or  phospholipins  have  been 
attached,  the  latter  of  proteins  in  combination  with  one  or  more  of 
the  higher  fatty  acids.  It  is  possible  that  the  forms  are  easily  dis- 
sociated and  vary  from  loose  and  transient  physical  aggregates  to 
relatively  more  stable  chemical  combinations.  Their  very  lability 
would  make  them  of  great  physiological  importance  in  cellular 
processes. 

The  conjugated  proteins  are  of  considerable  importance  from  the 
point  of  view  of  nonspecific  reactions.  On  injection  they  are  followed 
in  general  by  relatively  little  reaction,  but  the  organism  can  become 
sensitized  to  these  proteins  just  as  to  simple  proteins  of  the  first 
group.  When  the  conjugated  proteins  are  dissociated  from  their  non- 
protein  radicals  they  produce  a  far  greater  reaction  than  when  in 
the  conjugated  form.  Schittenhelm  and  his  associates  have  demon- 
strated this  with  the  chromoproteins. 


254  PROTEIN  THERAPY 

The  phosphoproteins  are  of  interest  because  casein — the  isolated 
protein  of  milk — belongs  in  this  category.  This  protein  has  been  used 
to  a  great  extent  for  the  nonspecific  reaction.  Casein  itself  is  followed 
by  little  or  no  general  reaction  when  injected  for  the  first  time.  It 
has  been  suggested  that  the  more  marked  reaction  obtained  with  milk 
injections  is  due  to  the  bacterial  content,  rather  than  due  to  the 
protein  of  the  milk  itself.  Casein  is  practically  the  only  one  of  the 
native  proteins  which  is  subject  to  the  action  of  erepsin,  both  of  the 
enzyme  of  the  intestinal  tract  and  the  erepsin-like  enzyme  occurring 
in  the  serum. 

The  nucleoproteins  occur  not  only  in  the  proteins  obtained  from 
nuclei  of  cells,  but  are  present  in  large  amounts  in  the  material  ob- 
tained from  bacterial  sources  in  which  the  nucleoprotein  occurs 
throughout  the  cell  body.  The  relation  of  these  substances  to  the  so- 
called  endotoxins  of  bacteria  is  still  uncertain,  v.  Groer  isolated 
a  nucleohiston  from  typhoid  bacilli  which  he  used  for  nonspecific 
injections. 

The  Derived  Proteins. — This  group  is  an  artificial  one  and  in- 
cludes all  the  decomposition  products  occurring  after  the  action  of 
chemical,  physical  or  biological  agents  (enzymes)  on  the  naturally 
occurring  proteins. 

In  the  first  group  are  included  the  proteins,  metaproteins  and 
coagulated  proteins,  that  is,  proteins  which  have  undergone  the  first 
alterations  following  the  action  of  heat,  acids,  etc.  This  group  has 
no  importance  from  the  therapeutic  standpoint. 

In  the  second  group  are  included  those  protein  derivatives  com- 
monly called  protein  split  products,  which  in  turn  are  classified  under 
three  groups — Proteoses,  Peptones  and  Peptids. 

THE  PROTEOSES  (ALBUMOSES). — These  represent  the  first  dissocia- 
tion products  of  the  albumins.  They  are  no  longer  heat  coagulable 
but  can  be  salted  out  by  concentrations  of  certain  salts  such  as  am- 
monium sulphate,  zinc  sulphate,  etc.  They  are  by  no  means  clearly 
defined  chemical  entities,  the  usual  preparations  obtained  by  precipi- 
tation including  mixtures  of  molecules  and  molecular  aggregates  vary- 
ing to  some  extent  in  size.  The  albumoses  are  roughly  divided  into 
two  groups,  primary  and  secondary  albumoses.  Of  these  the  primary 
proteases  more  closely  approximate  the  proteins  from  which  they  are 
derived;  they  are  precipitated  by  half  saturation  with  ammonium 
sulphate. 

The  Primary  Proteoses  can  in  a  general  way  be  divided  into  two 
groups  by  means  of  dialysis,  whereby  the  hetero-albumose  becomes 
insoluble,  or  by  the  addition  of  an  equal  amount  of  alcohol.  Hof- 
meister's  table  may  be  of  some  value  in  illustrating  the  differences 
in  behavior  of  these  higher  split  products  of  proteins. 

In  general  it  may  be  stated  that  the  primary  proteoses  are  more 
toxic  than  the  secondary  proteoses,  but  variations  occur,  depending 


APPENDIX 

Hofmeister'a  Table 


255 


Precipita- 
tion 

Water 
sol. 

Ale.   sol. 

Diffus- 
ibility 

Biuret 

Primary 
Albumoses      „ 

Ppt.  in 

Proto- 
Albumose 

Readily 
sol. 

Sol.  in 
80% 

Good 

+ 

(Proteoses) 

from  24  to 

42% 

Not 

Amm. 

sol 

Sulphate 

Hetero- 
Albumose 

BUI., 

but  sol. 
in  dil. 

Insol.  in 
32% 

Poor 

+ 

salt 

. 

sol. 

Deutero- 

54%  to 
62% 

A. 

Thio- 
Albumose 

Sol. 

Insol.  in 
60%  -70% 

+ 

"*     or 
Secondary 
Albumoses 

70%  to 
95% 

B. 

Albumose 
Syn- 

Sol. 

Vary 

+ 

100% 
+  Acid 

C. 
C- 

Albumose 

Sol. 

Sol.  in 
67%-80% 

- 

no  doubt  on  the  chemical  composition  of  the  original  protein  from 
which  the  split  products  are  derived.  Kaznelson  has  reported  observa- 
tions in  this  connection  with  protein  split  products  obtained  from 
fibrin,  silk,  casein,  etc.,  and  found  that  those  derived  from  fibrin  were 
most  toxic. 

The  Secondary  Proteoses  or  Deutero-albumoses,  have  been  used 
therapeutically  by  Liidke  and  include  the  protein  fragments  that  are 
precipitated  by  complete  saturation  with  ammonium  sulphate  after 
the  primary  proteoses  have  been  removed  by  half  saturation.  The 
group  is  an  indefinite  one  and  includes  a  number  of  fragments  evi- 
dently of  different  sizes  which  have  been  classified  as  A,  B  and  C  by 
Hofmeister,  as  Thio-albumose,  Synalbumose,  etc. 

Witte  Peptone,  which  has  been  frequently  studied  and  which  Nolf, 
Gow  and  others  have  made  use  of  for  therapeutic  injections,  consists 
of  a  digestion  mixture  in  which  albumoses  are  abundantly  found.  It 
is  said  to  be  prepared  by  the  digestion  of  fibrin.  From  it  the  primary 
and  secondary  proteoses  can  easily  be  prepared  by  salting  out  in 
proper  concentrations. 

PEPTONES. — These  are  further  hydrolytic  cleavage  products  soluble 
in  water,  not  coagulable  by  heat  nor  precipitable  by  ammonium  sul- 
phate; they  are  easily  diffusible  and  give  biuret  reactions.  They  differ 
greatly  in  toxicity. 

PEPTIDS. — The  simpler  compounds  of  amino-acids,  many  of  which 


256  PROTEIN  THERAPY 

have  been  synthetically  prepared  by  linking  two  or  more  amino  acids 
— di-peptids,  tri-peptids,  etc.  They  are  not  coagulable  by  heat,  are 
easily  soluble  and  may  still  give  a  biuret  reaction. 

The  Amino- Acids. — The  amino-acids  form  the  ultimate  molecular 
units  from  which  the  proteins  are  constructed.  They  are  grouped  into 
five  classes: — 

1.  The  Aliphatic  or  Mono-amino,  monocarboxylic  acids,  includ- 
ing glycocoll,  alenin,  valin,  etc. 

2.  The  Mono-amino,  dicarboxylic  acid  group  including  aspartic 
acid  and  glutamic  acid. 

3.  The  Isocylic,  amino-acids  such  as  tyrosin  and  phenyl  alanin. 

4.  The  Heterocylic,  amino-acids  including  histidin,  tryptophan, 
prolin,  etc. 

5.  The  Diamino-monocarboxylic   acid  group  with   arginin  and 
lysin. 

In  general  the  lower  split  products  of  the  proteins,  including  the 
amino  acids,  are  relatively  nontoxic  and  bring  about  little  or  no  re- 
action on  the  part  of  the  patient  when  injected;  the  compounds  con- 
taining the  various  ring  groupings  of  the  carbon  atom  as  well  as  the 
diamino  group  seem,  however,  to  be  exceptions.  Considerable  work 
has  recently  been  reported  by  Dale  and  his  associates  and  by  Koessler 
and  Hanke  in  connection  with  the  toxicity  of  histamin. 


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280  PROTEIN  THERAPY 

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Uin.  Wchnschr.,  1907,  xliv,  1209. 
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INDEX 


Abderhalden's  reaction,  101 
Abscess,  fixation,  of  Fochier,  3,  40,  42 

salt,  40 

Actinomycosis,  235 

Activating  agents  in  focal  reaction,  74 
Activation,  focal,  from  intracutaneous 
injections,  139 

non-specific,  88 

of  skin  reactivity,  129 
Acute  exanthemata,  139 
Adnexal  inflammation,  181 
Albumin  egg,  see  Ovalbumin 

serum,  21 
Albuminoids,  253 
Albumins,  252 
Albuminuria,  in  non-specific  reactions, 

56 
Albumoses,  25,  254 

Hoffmeister's  table  of,  255 

in  influenza,  195 

injection  of,  in  typhoid  fever,  158 

primary,  25,  254 

deutero-,  25 

secondary,  255 
Allergy,  130 
Amino-acids,  256 
Ammoniacal  copper  sulphate,  41 
Amylopsin,  28 

Anaphylactic  shock,  changes  in  coagu- 
lability of  blood  in,  216 
Anemia,  pernicious,  214 

secondary,  213 
Angina,  Vincent's,  205 
Angioneurotic  edema,  213 
Animal  serum,  normal,  17 
Anthrax,  185 
Antibacterial  sera,  18 
Antibodies,  and  the  reactions,  91 

in  nonspecific  reactions,  66 

resistance,  99 
Antiferments,  in  nonspecific  reactions, 

66 

Antigen,  of  Much,  36 
Antipyretics,  42 
Antistreptococcus  serum,  in  influenza, 

194 

Antitrypsin,  in  nonspecific  reactions,  66 
Antitoxins,  18 
Antiyeast  serum,  19 
Aolan,  23 
Arthigon,  27,  35 
Arthritis,  142 

gonorrheal,  171 

309 


Asthma,  210 

Autolysates,  tumor,  4,  29 
Autoserotherapy,  16,  20 
method  of  Gilbert,  4 

Bacillary  dysentery,  187,  189 

Bacterial    extracts    and    related    sub- 
stances, 13,  36 

Beard's  enzyme  treatment  of  cancer,  4, 
28 

Bee  stings,  41 

Beef  serum,  17 

Bibliography,  257 

Bier's  passive  hyperemia,  21 

Biological  alterations,  44 

Blister  serum,  20 

Blood,  16 

coagulability  of,  changes  in,  in  ana- 
phylactic  shock,  216 

Blood  letting,  16 

Blood  pressure  in  nonspecific  reactions, 
51 

Blood  serums,  16 

Blood  sugar  in  nonspecific  reactions,  63 

Blood  transfusion,  16 

Blood  vessels,  permeability  of,  in  non- 
specific reactions,  56 

Buboes,  180 

Carbuncles,  245 

Carcinoma,  218 

Beard's  enzyme  treatment  of,  4,  28 
nonspecific  injections  in,  111 

Carriers,  diphtheria,  185 
typhoid,  164 

Cartilage,  extract  from,  29 

Casein,  23,  24 

Caseosan,  23 

Cautery,  14 

Cerebral  lues,  207 

Cerebrospinal  fluid,  21 

Chicken  serum,  17 

Children,  diseases  of,  221 

Chill,  in  nonspecific  reactions,  47 

Cholera  vaccine,  34 

Chromoprpteins,  253 

Classificatipn  of  focal  reactions,  72 

Coagulability  of  blood,  in  anaphylactic 
shock,  216 

Coley's  fluid,  in  sarcoma,  4,  37 

Collateral  immunization,  33 

Colloidal  metals,  13,  37,  39 

Colloidal  therapy,  252 


310 


INDEX 


Colloids,   metal,  sensitization   of  skin 

to,  75 

Colon  bacillus  vaccine,  33,  172 
Contraindications  to  protein  therapy, 

249 

Convalescent  serum,  17 
Counterirritants,  12,  14 
Counterirritation,  14,  15 

Danysz's  method,  35 

Delirium  in  nonspecific  reactions,  54 

Depression  immunity,  44 

of  skin  reactivity,  128 
Dermatoses,  hysteric,  234 

of  pregnancy,  231 
Detoxication,  100 
Deutero-albumoses,  25,  172,  255 

dosage  of ,  26 
Deutschmann  serum,  19 
Diphasic  character  of  focal  reaction,  77 
Diphtheria,  185 

antitoxin,  18 
in  influenza,  194 

carriers,  185 

vaccines,  34 

Diphtheroid  vaccines,  34 
Distilled  water  injections,  41 
Diuresis  in  nonspecific  reactions,  56 
Doellken's  theory,  86,  89 
Dysentery,  acute,  intravenous  method 
in,  188 

bacillary,  187,  189 

milk  injections  in,  189 

vaccine,  33 

vaccinotherapy  in  old  chronic  cases, 
188 

Ear  diseases  and  infections,  218 

Eczema,  234 

Edema,  angioneurotic,  213 

Effusions,  pleural,  20 

Egg  albumin,  see  Oyalbumin 

Encephalitis,  lethargic,  195 

Endocarditis,  198 

Endogenous     localized     inflammatory 

processes,  73 
Enzymes,  13,  28 

and  the  reaction,  91 

in  nonspecific  reactions,  64 

in  pathological  conditions,  100 

in  skin  reactions,  131 

proteolytic,  102 

serum,  102 

Enzyme  treatment  of  cancer,  4,  28 
Epididymitis,  174 

local  injection  in,  178 
Epilepsy,  228 
Ereptase,  102 
Ergotropie,  12 
Erysipelas,  191 
Erythema  nodosum,  234 
Erythrocytes  in  nonspecific  reactions, 
63 


Esophylaxis,  135 
Exophylaxis,  135 
Extracts,  tissue,  13,  29 
Exudates,  pleural,  20 
Eye,  diseases  of,  236 

Ferment-antiferment  balance,  108 
Fibrinogen  in  nonspecific  reaction,  63 
Fixation  abscess  of  Fochier,  3,  40,  42 
Focal   activation   from   intracutaneous 

injections,  139 
Focal  reactions,  70 

activating  agents,  74 

classification  of,  72 

diphasic  character  of,  75 

in  tuberculosis,  78,  79 

mechanism  of,  77 

specificity  of,  72 

therapeutic  applications  of,  81 
Fochier,  fixation  abscess  of,  3,  40,  42 
Foci,  pulmonary  of  tuberculous  origin, 
72 

non-tuberculous  inflammatory,  73 

tuberculous,  78 

vascularized  inflammatory,  77 
Fontanelle,  14 
Formalin,  41 
Furunculosis,  234 

Gas,  mustard,  116 
war,  115 

Gelatin,  24 

General  paralysis,  treatment  of,  224 

Glandular  activity  in  nonspecific  reac- 
tions, 54 

Glaucoma,  237 

Globulins,  252 

Glucoproteins,  253 

Glucose  solutions,  41 

Glutelins,  253 

Glycoproteins,  253 

Goat  serum,  17 

Gonococcus  vaccines,  34,  171 

Gonorrhea  and  its  complications,  170 
local  injection  in,  178 
provocation  reaction  in,  181 

Gonorrheal  arthritis,  171 

Gout,  147 

Hay  fever,  210 

Headache  in  nonspecific  reactions,  54 

Heliotherapy,  43,  137 

Hemoglobins,  253 

Hemorrhagic  diathesis,  214 

Herd  reaction,  70 

Herpes  in  nonspecific  reactions,  53 

Heterobacteriotherapy,  8 

Heterovaccination,  245 

Heterovaccines  in  typhoid  fever,  154 

in  paratyphoid  fever,  154 
Hetol,  41 
Histamin,  27 
Histones,  253 


INDEX 


311 


Hoffmann's  theory,  136 
Hoffmeister's  table  of  albumoses,  255 
Horse  serum,  17 
Human  milk,  23 

serum,  normal,  16 
Hyperemia,  Bier's,  21 
Hypersensitiveness  of  the  tuberculous, 

79 
Hypertonic  salt  solutions,  39 

in  influenza,  195 
Hypotonic  salt  solutions,  39 
Hysteric  dermatoses,  234 

Immune  serum,  17 
Immunity,  depression,  44 
Immunization,  collateral,  33 

nonspecific,  32 

Indications  for  protein  therapy,  247 
Infections,  protozoal,  206 

spirochetal,  206 
Inflammation,  242 

adnexal,  181 

local,  reaction  in,  113 

of  bacterial,  origin,  116 

of  nonbacterial  origin,  reaction  in,  115 
Inflammatory  foci,  non  tuberculous,  73 

vascularized,  77 

Inflammatory  processes,  localized,  en- 
dogenous, 73 

localized,  traumatic,  73 
Influenza,  192 

albumoses  in,  195 

antistreptococcus  serum  in,  194 

colloidal  metals  in,  192 

convalescent  serum  in,  194 

diphtheria  antitoxin  in,  194 

fixation  abscess  in,  193 

hypertonic  salt  solution  in,  195 

milk  injection  in,  194 

Much's  vaccine  in,  195 

normal  serum  in,  194 

sera  in,  194 

turpentine  injection  in,  193 

vaccines,  34,  194 
Internal  medicine,  relation  of  skin  to, 

134 
Intoxication  by  protein-split  products, 

99 

Intravenous  injection  of  typhoid  vac- 
cine, 153 
Iodides,  41 

infection  by,  local  effects  of,  21 
Iritis,  238,  239 

Jarisch-Herxheimer  reaction,  75 
Joint  fluid,  21 

Keratitis,  236,  237,  238 

Lecithoproteins,  253 
Lethargic  encephalitis,  195 
Leukocytes  in  nonspecific  reactions,  58 
Leukocytic  extracts,  28 
injection  of.  4 


Leukocytosis,  95 
Leukoproteases,  102 
Light  rays,  43 

effect  of,  on  skin,  136 
Lipase,  64 
Liproproteins,  253 

Local  inflammation,  reaction  in,  113 
Local  injections,  in  gonorrhea,  178 

in  epididymitis,  178 
Local  reactions,  70 

Localized  inflammatory  processes,  en- 
dogenous, 73 

traumatic,  73 
Lues,  cerebral,  207 

Lymph,  concentration  in  nonspecific  re- 
actions, 59 

enzymes  in  nonspecific  reactions,  64 

volume  in  nonspecific  reactions,  59 
Lymphagogue  effect  in  nonspecific  re- 
actions, 57 
Lysins,  71 

Malaria,  208 

activation,  208 

therapy,  208 

Malignant  neoplasms,  218 
Measles,  196 

Mechanism  of  focal  reaction,  77 
Mechanism  of  reaction,  theories  of,  83 

Nolf's  theory,  91 

Starkenstein's  theory,  96 

Weichardt's  theory,  84 

Wright's  theory,  84 
Meningitis,  tuberculous,  203 
Meningococcus  vaccines,  34,  172 
Menstruation,  in  nonspecific  reactions, 

53 
Metallic  colloids,  13,  37,  39 

sensitization  of  skin  to,  75 
Milk,  54 

human,  23 

injections  of,  22,  23 

in  typhoid  fever,  158 
Moxa,  14 
Much's  antigen,  36 

vaccine  in  influenza,  195 
Mustard  gas,  116 
Myositis,  178 

Nausea,  in  nonspecific  reactions,  53 

Neoplasms,  malignant,  218 

Nephritis,  217 

Nervous  irritability,  in  nonspecific  re- 
actions, 53 

Neuritis,  217 

Neuro-arthropathies,  syphilitic,  207 

Nitrogen  metabolism,  in  nonspecific  re- 
actions, 54 

Nolf's  theory  of  the  mechanism  of  the 
reaction,  91 

Nonspecific  activation,  88 
agents,  12 
immunization,  32 


312 


INDEX 


Nonspecific  injections  in  carcinoma,  111 
Nonspecific  reactions,  46 
albuminuria  in,  56 

antibodies  in,  66 

antiferment  in,  66 

blood  pressure  in,  51 

blood  sugar  in,  63 

chill  in,  47 

delirium  in,  54 

diuresis  in,  56 

erythrocytes  in,  63 

fibrinogen  in,  63 

glandular  activity  in,  54 

headache  in,  54 

herpes  in,  53 

leukocytes  in,  58 

lipase  in,  64 

lymphagogue  effect  of,  57 

menstruation  in,  53 

nausea  in,  53 

nervous  irritability  in,  53 

nitrogen  metabolism  in,  54 

peptidase  in,  64 

permeability  of  blood  vessels  in,  56 

platelets  in,  63 

protease  in,  64 

pulse  in,  50 

serum  enzymes  in,  64 

spleen  in,  53 

sweating  in,  52 

temperature  curve  in,  48 

thrombokinase  in,  63 

urticaria  in,  53 

vomiting  in,  53 

Wassermann  reaction  in,  69 

weight  of  patient  and,  55 
Non-tuberculous     inflammatory     foci, 

73 
Normal  salt  solution,  local  effects  of. 

21 
Normal  serum,  animal,  17 

human,  16 
Nucleic  acid,  24 
Nucleins,  24 
Nucleohexyl,  25 
Nucleoproteins,  253,  254 

Omnicellular  plasmaactivation,  84 
Ophthalmoblenorrhea,  238 
Orchitis,  196 
Organotherapy,  29 
Otology,  218 
Ovalbumin,  21 

Paralysis,  general,  treatment  of,  224 
Paraspecific  serum  therapy,  18 
Parotitis,  196 
Paratyphoid   fever,  heterovaccines  in, 

154 

treatment  of,  153,  169 
Pediatrics,  221 
Pemphigus,  234 


Peptidase,  102 

in  nonspecific  reactions,  84 
Peptids,  255 
Peptone  effect,  26 
Peptone  shock,  26 
Peptones,  255 

Witte,  27,  255 

Permeability  of  blood  vessels  in  non- 
specific reactions,  56 
Pernicious  anemia,  214 
Phlegmons,  245 
Phosphoproteins,  253,  254 
Photodynamic  agents,  43 
Phylacogens,  37 
Phlyctenular  disease,  237 
Plant  proteins,  13,  24 
Plasma-activation,  12,  76,  77,  80,  84 

omnicellular,  84 
Plasma  serum,  19 

Platelets  in  nonspecific  reactions,  63 
Pleural  effusions,  20 
exudates,  20 
transudates,  20 
Pneumonia,  103,  120,  196, 
nonspecific  reaction  in,  123 

therapy  in,  120 
Pneumococcus  antolysate,  37 

vaccines,  34 

Pregnancy,  dermatoses  of,  231 
Prolamines,  253 
Protamines,  253 
Protease,  102 

in  non-specific  reactions,  64 
Proteins,  13,  21,  252 
and  their  split  products,  252 
classification  of,  252 
compound,  253 
conjugated,  253 
derived,  254 
native,  21,  252 
plant,  13,  24 
simple,  252 
Protein-split  products,  13,  25 

intoxication  by,  99 
Protein-therapy,  25 
contraindications  to,  249 
history  of,  1 
indications  for,  247 
modem  conceptions  of,  7 
Proteolytic  enzymes,  102 
Proteoses,  25,  254 
Protozoal  infections,  206 
Provocative     reaction     in     gonorrhea, 

181 

Psoriasis,  231,  234 
Puerperal  infections,  196 
Pulmonary  foci  of  tuberculosis,  72 
Pulse,  in  nonspecific  reactions,  50 
Purpura,  215 
Pyelitis,  217 
Pyelonephritis,  217 
Pyocyaneus  vaccines,  34 
Pyretotherapy,  178,  182 


INDEX 


313 


Radium,  43 

Reaction,  Abderhalden's,  101 
antibodies  and,  92 
enzymes  and,  91 
focal,  activating  agents  in,  74 
in    inflammations    of    non-bacterial 

origin,  115 
local,  70,  113 

probable  mechanism  of,  99 
detoxication,  100 
ferment-antiferment  balance,  108 
intoxication  by  protein-split  prod- 
ucts, 99 

serum  enzymes,  102 
thermoregulatory  mechanism  and,  91 
Reading  bacillus,  243 
Relapsing  fever,  206 
Resistance,  antibody,  100 
Retinitis,  240 
Roentgen  rays,  43 

Salt  abscess,  40 

Salt  solutions,  hypertonic,  39 

hypotonic,  39 

normal,  effects  of,  21 
Sanarthrit,  29,  147 
Sarcoma,  218 

Coley's  fluid  in,  4,  37 
Scarlet  fever,  198 
Schafer's  vaccine,  37 
Scurvy,  216 

Secondary  anemia,  213 
Selective  stimulation,  88 
Sensitization,  130 

of  skin  to  metallic  colloids,  75 
Sepsis,  non-specific  therapy  in,  125 
Septicemia,  200 
Serum,  or  Serums,  12,  16 

albumin,  21 

antibacterial,  18 

antistreptococcus,  in  influenza,  194 

antiyeast,  19 

beef,  17 

blister,  20 

blood,  16 

chicken,  17 

concentration  of,  in  nonspecific  reac- 
tions, 59 

convalescent,  17 
in  influenza,  194 

Deutschmann,  19 

enzymes,  102 

in  nonspecific  reactions,  64 

goat,  17 

horse,  17 

immune,  17 

in  influenza,  194 

local  effects  of,  21 

normal,  animal,  17 
human,  16 
in  influenza,  194 

paraspecific,  18 

plasma,  19 


Serum,  or  Serums,  sheep,  17 

tuberculosis,  19 
Serum  therapy,  paraspecific,  18 
Seton,  14 
Sheep  serums,  17 
Skin,  diseases,  230 
effect  of  light  on,  136 
reactions,  enzymes  in,  132 
reactivity,  128 
activation,  129 
depression,   128 
relation    of,    to    internal    medicine, 

134 

to  nonspecific  resistance,  128 
sensitization  of,  to  metallic  colloids, 

Smallpox,  201 
Snake  venom,  41 
Solusin,  41 

Specificity  of  focal  reactions,  72 
Spirochetal  infections,  206 
Spleen  in  nonspecific  reactions,  53 
Staphylococcus  vaccines,  34 
Starkenstein's  theory  of  the  mechan- 
ism of  the  reaction,  96 
Stimulation,  selective,  89 
Streptococcus  vaccines,  34 
Sugar  solutions,  41 
Sweating  in  nonspecific  reactions,  52 
Syphilides,  231 
Syphilis,  139,  206 

cerebral,  207 
Syphilitic   neuro-arthropathies,   207 

Tabes,  treatment  of,  224,  227 
Tebelon,  36 

Temperature  curve,  in  nonspecific  reac- 
tions, 48 

Terpichin,  42,  180 
Tetanus,  201 

Therapeutic  applications  of  focal  reac- 
tion, 81 

Thermocautery,  14 

Thermoregulatory  mechanism,  and  re- 
action, 90 

Thrombokinase    in    nonspecific    reac- 
tions, 63 

Tissue  extracts,  13,  29 
Trachoma,  236,  237 
Transfusion,  blood,  16 
Transudates,  pleural,  20 
Traumatic  inflammatory  processes,  lo- 
calized, 73 
Trench  fever,  201 
Trichophyton  infection,  232 
Trypsin,  28 
Tryptase,  102 
Tuberculin,  36 

in  gonorrhea,  179 

reaction,  75 
Tuberculosis,  202 

foci  of,  72,  78 

serum,  19 


314 


INDEX 


Tuberculous,    general    hypersensitive- 
ness  of  the,  79 
Tuberculous  meningitis,  203 
Tumor,  autolysates,  4,  29 
Turpentine,  42 
Typhin,  36,  163 
Typhoid  carriers,  164 
Typhoid  fever,  117 
albumose  injections  in,  158 
heterqvaccines  in,  154 
injections  of  milk  in,  158 
intravenous    injections    of    vaccine, 

153 

treatment  of,  153,  165 
comparative  results,  160 
heterovaccines  in,  154 
intravenous  injections  in,  153 
milk  in,  158 

therapeutic  precautions  in,  167 
vaccines  in,  33,  153 
ulcers,  167 
Typhoid  ulcers,  167 

vaccines,  33,  153 
Typhus  fever,  203 

Ulcers,  245 

typhoid,  167 
Urticaria,  in  nonspecific  reactions,  53 

Vaccines,  13,  30 
cholera,  34 
colon  bacillus,  33,  172 


Vaccines,  diphtheria,  34 

diphtheroid,  34 

dysentery,  33,  188 

gonococcus,  34,  171 

in  influenza,  194,  195 

meningococcus,  34,  172 

mixed,  35 

pneumococcus,  34 

pyocyaneus,  34 

staphylococcus,  34 

streptococcus,  34 

typhoid,  33,  153 
Vaccine  therapy,  results  of,  31 
Vaccinurin,  35 

Vascularized  inflammatory  foci,  77 
Venom,  snake,  41 
Vincent's  angina,  205 
Vomiting,  in  nonspecific  reactions,  53 

War  gas,  115 

Wassermann  reaction,  effect  of  non- 
specific reactions  on,  69 

Weichardt's  theory  of  plasma  activa- 
tion, 77,  84 

Weight  of  patient,  and  nonspecific  re- 
actions, 55 

Weil's  disease,  207 

Witte  peptone,  27,  255 

Wright's  theory  of  the  mechanism  of 
the  reaction,  93 

Yeast,  13,  43 


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1  6  1992 


LIBRARY,  UNIVERSITY  OF  CALIFORNIA,  DAVIS 

Book  Slip-'25m-6,'66(G3S55s4)458 


^07320 


HEAITM 


Call  Number: 

QW815 
P4 


N9  507320 


Petersen,    W.F. 

Protein   therapy 
and   nonspecific 
resistance. 


QW815 
P4 


HEALTH 

SCIENCES 

LIBRARY 


LIBRARY 

UNIVERSITY  OF   CALIFORNIA 
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